Crystalline salt forms

ABSTRACT

Disclosed are various crystalline salt forms of D-Arg-Dmt-Lys-Phe-NH 2 .

RELATED APPLICATION

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 62/307,095, filed Mar. 11, 2016.

BACKGROUND

Through oxidative phosphorylation, mitochondria convert nutrients andoxygen into adenosine triphosphate (ATP), the chemical transporter ofenergy in most aerobic organisms. The electron transport chain (ETC) ofthe mitochondria represents the primary source of ATP, as well as asource of reactive oxygen species (ROS). Mitochondrial dysfunctionresults in less ATP production and, as a result, insufficient energy tomaintain the cell. Such dysfunction also results in excessive ROSproduction, spiraling cellular injury, and ultimately apoptosis of thecell. Mitochondrial dysfunction, is a key element believed to be at theroot of a variety of serious, debilitating diseases.

Natural antioxidants such as coenzyme Q and vitamin E have been shown toprovide some protection of the cell from damage induced by elevated ROSlevels associated with mitochondrial dysfunction. However, antioxidantsor oxygen scavengers have also been shown to reduce ROS to unhealthylevels and may not reach the ETC in sufficient concentrations to correctthe mitochondrial imbalance. Therefore, there is a need for novelcompounds that can selectively target the ETC, restore efficientoxidative phosphorylation, and, thereby, address mitochondrial diseaseand dysfunction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a XRPD pattern of a hydrochloride salt of Compound I.

FIG. 2 depicts a XRPD pattern of a tartrate salt of Compound I.

FIG. 3 depicts a XRPD pattern of a mesylate salt of Compound I.

FIG. 4 depicts a XRPD pattern of a malate salt of Compound I.

FIG. 5 depicts a XRPD pattern of a tosylate salt of Compound I.

FIG. 6 depicts a XRPD pattern of a fumarate salt of Compound I.

FIG. 7 depicts a XRPD pattern of a cholesteryl sulfate Pattern 1(Methanol).

FIG. 8 depicts a XRPD pattern of a cholesteryl sulfate Pattern 2(Acetonitrile:Ethylene glycol (90:10 v/v)).

FIG. 9 depicts a XRPD pattern of a tosylate salt of Compound I Pattern 1(Acetonitrile:ethyleneglycol (90:10 v/v)).

FIG. 10 depicts a XRPD pattern of a tosylate salt of Compound I Pattern2 (2-propanol).

FIG. 11 depicts a XRPD pattern of a mesylate salt of Compound I Pattern1 (Dichloromethane).

FIG. 12 depicts a XRPD pattern of a mesylate salt of Compound I Pattern2 (Acetone:water(90:10 v/v)).

FIG. 13 depicts a XRPD pattern of an oxalate salt of Compound I Pattern1 (2-propanol).

FIG. 14 depicts a XRPD pattern of an oxalate salt of Compound I Pattern2 (Acetone:water(90:10 v/v)).

FIG. 15 depicts a XRPD pattern of an esylate salt of Compound I Pattern1 (2-Propanol).

FIG. 16 depicts a XRPD pattern of an esylate salt of Compound I Pattern2 (Anisole).

FIG. 17 depicts experimental a XRPD pattern of a fumarate salt ofCompound I Pattern 1 (2-propanol).

FIG. 18 depicts a XRPD pattern of a fumarate salt of Compound I Pattern2 (Acetone:water(90:10 v/v)).

FIG. 19 depicts a XRPD pattern of a fumarate salt of Compound I Pattern3 (2-propanol/water (re-preparations)).

FIG. 20 depicts a XRPD pattern of a fumarate salt of Compound I Pattern4 (2-propanol/water (scale-up)).

FIG. 21 depicts a XRPD pattern of a fumarate salt of Compound I Pattern5 (Pattern 4 after slurrying in water).

FIG. 22 depicts a XRPD pattern of a fumarate salt of Compound I Pattern6 (Acetonitrile during re-preparations).

FIG. 23 depicts a XRPD pattern of a fumarate salt of Compound I Pattern7 (1-butanol during re-preparations).

FIG. 24 depicts a XRPD pattern of a fumarate salt of Compound I Pattern8 (1-propanol during re-preparations).

FIG. 25 depicts a XRPD pattern of a benzoate salt of Compound I Pattern1 (2-propanol).

FIG. 26 depicts a XRPD pattern of a succinate salt of Compound I Pattern1 (Acetone:Water (90:10 v/v)).

FIG. 27 depicts a view of MTP-131 tosylate, Pattern 2 asymmetric unitwith atom labelling. All non-hydrogen atoms are shown with thermalellipsoids set at the 50% probability level.

FIG. 28 depicts a view of MTP-131 parent molecule with atom labels. Allnon-hydrogen atoms are shown with thermal ellipsoids set at the 50%probability level.

FIG. 29 depicts an ORTEP view of MTP-131 tosylate, Pattern 2 asymmetricunit with atom labels. All non-hydrogen atoms are shown with thermalellipsoids set at the 50% probability level.

FIG. 30 depicts an ORTEP view of MTP-131 parent molecule with atomlabels. All non-hydrogen atoms are shown with thermal ellipsoids set atthe 50% probability level.

FIG. 31 depicts Hydrogen bond clashing between adjacent hydrogen atomsof parent MTP-131, Pattern 2 molecules. All non-hydrogen atoms are shownwith thermal ellipsoids set at the 50% probability level. (SymmetryCode: (i) +x, +y, −1+z).

FIG. 32 depicts a view of unit cell a axis of MTP-131, Pattern 2containing complete molecules. All atoms are shown with thermalellipsoids set at the 50% probability level.

FIG. 33 depicts a view of unit cell a axis of MTP-131, Pattern 2containing complete molecules. All atoms are shown with thermalellipsoids set at the 50% probability level.

FIG. 34 depicts a view of unit cell c axis of MTP-131, Pattern 2containing complete molecules. All atoms are shown with thermalellipsoids set at the 50% probability level.

FIG. 35 depicts a simulated XRPD 2θ diffractogram of MTP-131 tosylate,Pattern 2.

FIG. 36 depicts a comparison of MTP-131 tosylate, Pattern 2, andsimulated MTP-131 tosylate, Pattern 2 XRPD 2θ diffractograms.

DETAILED DESCRIPTION

The present invention features salts of Compound I

MTP-131; D-Arg-Dmt-Lys-Phe-NH2). Compound 1 has been shown to affect themitochondrial disease process by helping to protect organs fromoxidative damage caused by excess ROS production and to restore normalATP production.

A crystalline form of a salt of Compound I can be used tomodulate/improve the physicochemical properties of the compound,including but not limited to solid state properties (e.g.,crystallinity, hygroscopicity, melting point, or hydration),pharmaceutical properties (e.g., solubility/dissolution rate, stability,or compatibility), as well as crystallization characteristics (e.g.,purity, yield, or morphology).

In certain embodiments, the present invention provides a pharmaceuticalpreparation comprising a crystalline salt of Compound (I) and one ormore pharmaceutically acceptable excipients. In certain embodiments, thepharmaceutical preparations may be for use in treating or preventing acondition or disease as described herein.

In certain embodiments, the polymorph of the crystalline salt ischaracterized by powder X-ray diffraction (XRPD). θ represents thediffraction angle, measured in degrees. In certain embodiments, thediffractometer used in XRPD measures the diffraction angle as two timesthe diffraction angle θ. Thus, in certain embodiments, the diffractionpatterns described herein refer to X-ray intensity measured againstangle 2θ.

In certain embodiments, a crystalline salt of Compound (I) is notsolvated (e.g., the crystal lattice does not comprise molecules of asolvent). In certain alternative embodiments, a crystalline salt ofCompound (I) is solvated. In some cases, the solvent is water.

In one aspect, the invention features a crystalline form of Compound Iwhich has characteristic peaks in the powder X-ray diffraction (XRPD)pattern as shown in any one of FIGS. 1-26.

In another aspect, the invention features a crystalline form of CompoundI which has characteristic peaks in the powder X-ray diffraction (XRPD)pattern at values of two theta (° 2θ) as shown in any one of Tables1-20.

The relative intensity, as well as the two theta value, of each peak inTables 1-20, as well as FIGS. 1-26, may change or shift under certainconditions, although the crystalline form is the same. One of ordinaryskill in the art should be able to readily determine whether a givencrystalline form is the same crystalline form as described in one ofTables 1-20, as well as FIGS. 1-26 by comparing their XRPD data.

In another aspect, the invention features a crystalline form of CompoundI which has characteristic peaks in the powder X-ray diffraction (XRPD)pattern at values of two theta (° 2θ) as shown in any one of Tables11-18.

In another aspect, the invention features a crystalline form of CompoundI which has characteristic peaks in the powder X-ray diffraction (XRPD)pattern at values of two theta (° 2θ) as shown in any one of Tables 5,6, 9 and 10.

In another aspect, the invention features a crystalline form of CompoundI which has characteristic peaks in the powder X-ray diffraction (XRPD)pattern at values of two theta (° 2θ) as shown in any one of Tables 1-2,3-4, 7-8, 19 and 20.

In yet another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 3.

In another aspect, the invention features a crystalline form of amesylate salt Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.0,10.4, 11.0, 12.0, 14.9, 19.3, 20.4, and 21.4.

In another aspect, the invention features a crystalline form of amesylate salt Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.0,10.4, 11.0, 12.0, 14.9, 15.7, 18.8, 19.3, 20.4, 20.8, 21.2, 21.4, 21.6,22.0, 22.5, 22.9, 25.9, and 26.4.

In yet another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 11.

In yet another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 5.

In another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 3.2,4.3, 6.0, 12.8, 17.5, 18.9, 20.6, 21.4, and 22.7.

In another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 3.2,4.3, 6.0, 12.0, 12.4, 12.8, 14.6, 15.8, 15.9, 17.5, 18.4, 18.9, 19.4,19.8, 20.1, 20.6, 21.4, 22.7, 23.2, 23.8, 24.8, 25.4, and 26.1.

In yet another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 12.

In yet another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 6.

In yet another aspect, the invention features a crystalline form of amesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 5.

In another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 11.6,12.2, 13.4, 15.4, 17.0, 20.2, 22.4, 22.7, and 23.1.

In another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.3,11.6, 12.2, 13.4, 14.7, 15.4, 16.1, 17.0, 18.9, 20.2, 22.4, 22.7, and23.1

In yet another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 9.

In yet another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 3.

In another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.5,12.0, 13.0, 13.3, 15.7, 17.3, 19.4, 20.5, and 23.1.

In another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.5,11.6, 11.8, 12.0, 13.0, 13.3, 15.0, 15.7, 15.9, 17.3, 19.4, 19.6, 20.5,22.4, 22.8, 23.1, and 23.7.

In yet another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 10.

In yet another aspect, the invention features a crystalline form of atosylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 4.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 6.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 3.6,12.0, 16.0, 21.2, 23.0, 23.3, 24.7, 24.9, and 25.7.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 3.6,7.2, 11.1, 12.0, 13.2, 16.0, 17.9, 18.3, 19.0, 19.4, 21.2, 23.0, 23.3,24.7, 24.9, 25.7, 26.1, and 28.6.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 17.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 11.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 4.2,11.3, 11.7, 12.4, 14.8, 17.0, 17.2, 20.7, 22.6, 23.3, 23.6, 24.1, 24.5,and 25.0.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 4.2,5.3, 10.3, 11.3, 11.7, 12.0, 12.4, 12.7, 13.0, 13.3, 14.8, 15.5, 15.8,16.1, 17.0, 17.2, 18.1, 20.7, 21.2, 22.0, 22.3, 22.6, 23.3, 23.6, 24.1,24.5, 25.0, 25.6, 26.0, and 28.6.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 18.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 12.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 4.6,11.2, 14.6, 19.9, 20.5, 24.2, 24.6, and 25.2.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 4.6,11.2, 14.6, 19.3, 19.9, 20.3, 20.5, 22.8, 23.1, 23.3, 23.6, 24.2, 24.3,24.6, 25.2, 25.6, 26.5, and 27.3.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 19.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 13.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 11.4,14.0, 19.6, 19.8, 22.9, 23.2, 24.3, and 24.5.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 11.4,13.3, 14.0, 16.0, 16.2, 19.6, 19.8, 21.6, 22.4, 22.9, 23.2, 23.6, 24.3,24.5, 25.6, and 26.6.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 20.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 14.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 12.3,21.0, 23.2, 24.0, 24.7, 25.0, 25.4, 26.0, 26.4, and 27.5.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.6,12.0, 12.3, 13.1, 13.6, 16.1, 19.6, 20.5, 21.0, 21.5, 23.2, 24.0, 24.7,25.0, 25.4, 26.0, 26.4, 27.5, 28.0, and 28.7.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 21.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 15.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 21.5,22.2, 23.1, 23.9, 24.1, 24.6, 25.2, and 26.0.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 13.4,16.3, 18.5, 21.5, 22.2, 23.1, 23.6, 23.9, 24.1, 24.6, 25.2, 26.0, 26.9,and 28.9.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 22.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 16.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.6,12.3, 13.6, 16.0, 19.2, 19.6, 20.4, 21.0, 21.1, 22.3, 23.2, 24.0, 25.3,and 26.0.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 6.6,12.3, 13.6, 16.0, 17.7, 18.1, 19.2, 19.6, 20.4, 21.0, 21.1, 22.3, 23.2,24.0, 24.6, 25.0, 25.3, 26.0, 26.3, and 27.4.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 23.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 17.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 13.2,20.3, 22.7, 21.4, 21.9, 23.6, 24.0, 24.4, and 25.6.

In another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 9.4,11.2, 13.2, 18.6, 20.3, 21.4, 21.7, 21.9, 22.7, 23.2, 23.6, 24.0, 24.4,25.6, 26.8, and 28.5.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 24.

In yet another aspect, the invention features a crystalline form of afumarate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 18.

In another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern at values of two theta (°2θ) of 5.0, 5.8, 11.9, 12.3, 12.6, 16.1, 16.8, and 17.0.

In another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern at values of two theta (°2θ) of 5.0, 5.8, 10.5, 11.9, 12.3, 12.6, 13.2, 16.1, 16.8, 17.0, and19.1

In yet another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern as shown in FIG. 7.

In yet another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern at values of two theta (°2θ) as shown in Table 1.

In another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern at values of two theta (°2θ) of 7.4, 12.4, 13.1, 15.6, 16.3, 17.7, and 19.8.

In another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern at values of two theta (°2θ) of 7.4, 12.4, 13.1, 13.4, 14.4, 15.6, 16.3, 17.7, 19.5, and 19.8.

In yet another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern as shown in FIG. 8.

In yet another aspect, the invention features a crystalline form of acholesteryl sulfate salt of Compound I which has characteristic peaks inthe powder X-ray diffraction (XRPD) pattern at values of two theta (°2θ) as shown in Table 2.

In another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.0,7.3, 13.4, 17.3, 21.3, 22.5, 22.9, and 24.7.

In another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.0,7.3, 12.2, 13.2, 13.4, 15.0, 16.2, 17.3, 18.6, 20.1, 21.3, 22.5, 22.9,23.3, 24.4, and 24.7.

In yet another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 13.

In yet another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 7.

In another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 3.8,4.3, 8.1, 19.8, 20.7, 22.3, 24.9, and 25.6.

In another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 3.8,4.3, 7.0, 8.1, 18.2, 18.3, 19.1, 19.8, 20.3, 20.7, 21.1, 22.3, 22.8,23.2, 23.5, 24.0, 24.6, 24.9, and 25.6.

In yet another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 14.

In yet another aspect, the invention features a crystalline form of anoxalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 8.

In another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.4,9.8, 10.8, 18.8, 19.7, 21.1, 21.8, and 22.3.

In another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.4,9.8, 10.8, 11.8, 14.4, 15.1, 15.6, 17.2, 17.7, 18.8, 19.0, 19.7, 21.1,21.5, 21.8, and 22.3.

In yet another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 15.

In yet another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 9.

In another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.4,10.8, 11.0, 14.5, 17.3, 18.7, 19.6, 21.0, 21.4, and 22.1.

In another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.4,9.7, 10.8, 11.0, 14.5, 15.0, 16.0, 17.3, 17.7, 18.7, 19.6, 21.0, 21.4,22.1, and 24.0.

In yet another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 16.

In yet another aspect, the invention features a crystalline form of anesylate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 10.

In another aspect, the invention features a crystalline form of abenzoate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.1,10.2, 13.2, 14.0, 20.4, 21.9 and 25.3.

In another aspect, the invention features a crystalline form of abenzoate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.1,10.2, 11.9, 13.2, 13.8, 14.0, 16.0, 16.7, 20.4, 21.9, 23.1, 23.5, 24.5,and 25.3.

In yet another aspect, the invention features a crystalline form of abenzoate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 25.

In yet another aspect, the invention features a crystalline form of abenzoate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern at values of two theta (° 2θ) as shownin Table 19.

In another aspect, the invention features a crystalline form of asuccinate salt of Compound I which has characteristic peaks in thepowder X-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of4.2, 5.1, 6.6, 9.9, 14.1, 18.0, and 24.1.

In another aspect, the invention features a crystalline form of asuccinate salt of Compound I which has characteristic peaks in thepowder X-ray diffraction (XRPD) pattern at values of two theta (° 2θ) of4.2, 5.1, 6.6, 8.0, 9.9, 10.3, 13.1, 14.1, 14.6, 17.6, 18.0, 18.5, 19.0,19.9, 20.8, 22.2, 22.4, 23.4, and 24.1.

In yet another aspect, the invention features a crystalline form of asuccinate salt of Compound I which has characteristic peaks in thepowder X-ray diffraction (XRPD) pattern as shown in FIG. 26.

In yet another aspect, the invention features a crystalline form of asuccinate salt of Compound I which has characteristic peaks in thepowder X-ray diffraction (XRPD) pattern at values of two theta (° 2θ) asshown in Table 20.

In yet another aspect, the invention features a crystalline form of ahydrochloride salt of Compound I which has characteristic peaks in thepowder X-ray diffraction (XRPD) pattern as shown in FIG. 1.

In yet another aspect, the invention features a crystalline form of atartrate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 2.

In yet another aspect, the invention features a crystalline form of amalate salt of Compound I which has characteristic peaks in the powderX-ray diffraction (XRPD) pattern as shown in FIG. 4.

The term “substantially pure” as used herein, refers to a crystallinepolymorph that is greater than 90% pure, meaning that contains less than10% of any other compound, including the corresponding amorphouscompound or an alternative polymorph of the crystalline salt.Preferably, the crystalline polymorph is greater than 95% pure, or evengreater than 98% pure.

In one embodiment, the present invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (XRPD) pattern as shown in any one of FIGS. 1-26 and whichis substantially pure. For example, the crystalline form can be at least90% pure, preferably at least 95% pure, or more preferably at least 98%.

In another embodiment, the present invention features a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (XRPD) pattern at values of two theta (° 2θ) as shown in anyone of Tables 1-20 and which is substantially pure. For example, thecrystalline form can be at least 90% pure, preferably at least 95% pure,or more preferably at least 98%.

Methods of Making the Crystalline Salts

In certain embodiments, the invention relates to a method for thepreparation of a crystalline salt of a compound having the structure offormula (I), comprising a) providing a freebase mixture of a compound offormula (I) in a first organic solvent; b) contacting the freebasemixture with a reagent solution comprising an acid and optionally asecond organic solvent under conditions sufficient to form a mixturecomprising a salt of the compound of formula (I); and c) crystallizingthe salt of the compound of formula (I) from the mixture comprising asalt of the compound of formula (I).

In certain embodiments, the invention relates to a method for thepreparation of a crystalline salt of a compound having the structure offormula (I), comprising a) providing a first salt mixture of a compoundof formula (I) in a first organic solvent; b) contacting the first saltmixture with a reagent solution comprising an acid and optionally asecond organic solvent under conditions sufficient to form a mixturecomprising a second salt of the compound of formula (I); and c)crystallizing the second salt of the compound of formula (I) from themixture comprising a second salt of the compound of formula (I).

In certain embodiments, the invention relates to a method for thepreparation of a crystalline salt of a compound having the structure offormula (I), comprising a) providing a first mixture comprising aprotected form of a compound of formula (I) in a first organic solvent;b) contacting the first mixture with a reagent solution comprising anacid and optionally a second organic solvent under conditions sufficientto deprotect the protected form of the compound of formula (I) and toform a mixture comprising a salt of the compound of formula (I); and c)crystallizing the salt of the compound of formula (I) from the mixturecomprising a salt of the compound of formula (I).

In certain embodiments, the mixture comprising a salt of the compound offormula (I) formed in step b) is a solution. In certain embodiments, themixture formed in step b) is a slurry or a suspension.

In certain embodiments, the mixture comprising the salt of the compoundof formula (I) is a solution, and the step of crystallizing the saltfrom the mixture comprises bringing the solution to supersaturation tocause the salt of the compound of formula (I) to precipitate out ofsolution.

In certain embodiments, bringing the mixture comprising the salt of acompound of formula (I) to supersaturation comprises the slow additionof an anti-solvent, such as heptanes, hexanes, ethanol, or another polaror non-polar liquid miscible with the organic solvent, allowing thesolution to cool (with or without seeding the solution), reducing thevolume of the solution, or any combination thereof. In certainembodiments, bringing the mixture comprising the salt of a compound offormula (I) to supersaturation comprises adding an anti-solvent, coolingthe solution to ambient temperature or lower, and reducing the volume ofthe solution, e.g., by evaporating solvent from the solution. In certainembodiments, allowing the solution to cool may be passive (e.g.,allowing the solution to stand at ambient temperature) or active (e.g.,cooling the solution in an ice bath or freezer).

In certain embodiments, the preparation method further comprisesisolating the salt crystals, e.g., by filtering the crystals, bydecanting fluid from the crystals, or by any other suitable separationtechnique. In further embodiments, the preparation method furthercomprises washing the crystals.

In certain embodiments, the preparation method further comprisesinducing crystallization. The method can also comprise the step ofdrying the crystals, for example under reduced pressure. In certainembodiments, inducing precipitation or crystallization comprisessecondary nucleation, wherein nucleation occurs in the presence of seedcrystals or interactions with the environment (crystallizer walls,stirring impellers, sonication, etc.).

In certain embodiments, the freebase mixture of a compound of formula(I) in a first organic solvent is a slurry. In certain embodiments, thefreebase mixtures of a compound of formula (I) in a first organicsolvent is a solution.

In certain embodiments, the first organic solvent and the second organicsolvent, if present, comprise acetone, anisole, methanol, 1-butanol,2-butanone, iso-butanol, tert-butanol, sec- butanol, cyclopentylmethylester (CPME), benezotrifluoride (BTF), 1-propanol, 2-propanol(IPA), water, dichloromethane, anisole, acetonitrile, ethylene glycol,tert-butyl methyl ether (t-BME), DMSO, ethylene glycol, toluene,tetrahydrofuran (THF), heptane, acetonitrile, N,N-dimethylacetamide(DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane,2-ethoxy ethanol, heptane, isopropyl acetate, methyl acetate, 2-methylTHF, methyl isobutyl ketone (MIBK), 1-propanol, ethanol, ethyl acetate,hexanes, methyl acetate, isopropyl acetate, methylethyl ketone,1,4-dioxane, methyl cyclohexane, N-methyl-2-pyrrolidone (NMP), or anycombination thereof

In certain embodiments, the first organic solvent and the second organicsolvent, if present, are the same. In alterative embodiments, the firstorganic solvent and the second organic solvent, if present, aredifferent.

In certain embodiments, washing the crystals comprises washing with aliquid selected from anti-solvent, acetonitrile, ethanol, heptanes,hexanes, methanol, tetrahydrofuran, toluene, water, or a combinationthereof. As used herein, “anti-solvent” means a solvent in which thesalt crystals are insoluble, minimally soluble, or partially soluble. Inpractice, the addition of an anti-solvent to a solution in which thesalt crystals are dissolved reduces the solubility of the salt crystalsin solution, thereby stimulating precipitation of the salt. In certainembodiments, the crystals are washed with a combination of anti-solventand the organic solvent. In certain embodiments, the anti-solvent iswater, while in other embodiments it is an alkane solvent, such ashexane or pentane, or an aromatic hydrocarbon solvent, such as benzene,toluene, or xylene. In certain embodiments, the anti-solvent is ethanol.

In certain embodiments, washing the crystals comprises washing thecrystalline compound of formula (I) with a solvent or a mixture of oneor more solvents, which are described above. In certain embodiments, thesolvent or mixture of solvents is cooled prior to washing.

Pharmaceutical Compositions

In certain embodiments, the present invention relates to pharmaceuticalcompositions comprising a crystalline compound or salt of a compound offormula (I) and one or more pharmaceutically acceptable excipients.

Exemplary pharmaceutically acceptable excipients are presented herein,and include, for example binders, disintegrating agents, lubricants,corrigents, solubilizing agents, suspension aids, emulsifying agents,coating agents, cyclodextrins, and/or buffers. Although the dosage couldvary depending on the symptoms, age and body weight of the patient, thenature and severity of the disorder to be treated or prevented, theroute of administration and the form of the drug, in general, a dailydosage of from 0.01 to 3000 mg of the compound is recommended for anadult human patient, and this may be administered in a single dose or individed doses. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect.

The precise time of administration and/or amount of the composition thatwill yield the most effective results in terms of efficacy of treatmentin a given patient will depend upon the activity, pharmacokinetics, andbioavailability of a particular compound, physiological condition of thepatient (including age, sex, disease type and stage, general physicalcondition, responsiveness to a given dosage, and type of medication),route of administration, etc. However, the above guidelines can be usedas the basis for fine-tuning the treatment, e.g., determining theoptimum time and/or amount of administration, which will require no morethan routine experimentation consisting of monitoring the subject andadjusting the dosage and/or timing.

In certain embodiments, the individual to which the composition isadministered is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered as a pharmaceutical compositioncomprising, for example, a compound of the invention and apharmaceutically acceptable carrier. Pharmaceutically acceptablecarriers are well known in the art and include, for example, aqueoussolutions such as water or physiologically buffered saline or othersolvents or vehicles such as glycols, glycerol, oils such as olive oil,or injectable organic esters. In a preferred embodiment, when suchpharmaceutical compositions are for human administration, particularlyfor invasive routes of administration (i.e., routes, such as injectionor implantation, that circumvent transport or diffusion through anepithelial barrier), the aqueous solution is sterile and pyrogen-free,or substantially pyrogen-free. The excipients can be chosen, forexample, to effect delayed release of an agent or to selectively targetone or more cells, tissues or organs. The pharmaceutical composition canbe in dosage unit form such as tablet, capsule (including sprinklecapsule and gelatin capsule), granule, lyophile for reconstitution,powder, solution, syrup, suppository, injection or the like. Thecomposition can also be present in a transdermal delivery system, e.g.,a skin patch. The composition can also be present in a solution suitablefor topical administration, such as an eye drop, through ophthalmicmucous membrane administration or penetration of the corneal epithelium.

A pharmaceutically acceptable carrier can contain physiologicallyacceptable agents that act, for example, to stabilize, increasesolubility or to increase the absorption of a compound such as acompound of the invention. Such physiologically acceptable agentsinclude, for example, carbohydrates, such as glucose, sucrose ordextrans, antioxidants, such as ascorbic acid or glutathione, chelatingagents, low molecular weight proteins or other stabilizers orexcipients. The choice of a pharmaceutically acceptable carrier,including a physiologically acceptable agent, depends, for example, onthe route of administration of the composition. The preparation orpharmaceutical composition can be a self-emulsifying drug deliverysystem or a self-microemulsifying drug delivery system. Thepharmaceutical composition (preparation) also can be a liposome or otherpolymer matrix, which can have incorporated therein, for example, acompound of the invention. Liposomes, for example, which comprisephospholipids or other lipids, are nontoxic, physiologically acceptableand metabolizable carriers that are relatively simple to make andadminister.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial. Each carrier must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the patient. Some examples of materials which can serve aspharmaceutically acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations. In certain embodiments, pharmaceutical compositions of thepresent invention are non-pyrogenic, i.e., do not induce significanttemperature elevations when administered to a patient.

The term “pharmaceutically acceptable salt” refers to the relativelynon-toxic, inorganic and organic acid addition salts of the compounds.These salts can be prepared in situ during the final isolation andpurification of the compounds, or by separately reacting a purifiedcompound in its free base form with a suitable organic or inorganicacid, and isolating the salt thus formed. Representative salts includethe hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,tartrate, naphthylate, mesylate, glucoheptonate, lactobionate,laurylsulphonate salts, and amino acid salts, and the like. Preparationof the crystalline salts is detailed in the Examples, below (See, forexample, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.).

In other cases, the compounds useful in the methods of the presentinvention may contain one or more acidic functional groups and, thus,are capable of forming pharmaceutically acceptable salts withpharmaceutically acceptable bases. The term “pharmaceutically acceptablesalts” in these instances refers to the relatively non-toxic inorganicand organic base addition salts of a compound. These salts can likewisebe prepared in situ during the final isolation and purification of thecompound, or by separately reacting the purified compound in its freeacid form with a suitable base, such as the hydroxide, carbonate, orbicarbonate of a pharmaceutically acceptable metal cation, with ammonia,or with a pharmaceutically acceptable organic primary, secondary, ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum salts,and the like. Other representative salts include the copper and ironsalts. Representative organic amines useful for the formation of baseaddition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine, and the like (see, forexample, Berge et al., supra).

A pharmaceutical composition (preparation) can be administered to asubject by any of a number of routes of administration including, forexample, orally (for example, drenches as in aqueous or non-aqueoussolutions or suspensions, tablets, capsules (including sprinkle capsulesand gelatin capsules), boluses, powders, granules, pastes forapplication to the tongue); absorption through the oral mucosa (e.g.,sublingually or buccally); anally, rectally or vaginally (for example,as a pessary, cream or foam); parenterally (including intramuscularly,intravenously, subcutaneously or intrathecally as, for example, asterile solution or suspension); nasally; intraperitoneally;subcutaneously; transdermally (for example as a patch applied to theskin); and topically (for example, as a cream, ointment or spray appliedto the skin, or as an eye drop). The compound may also be formulated forinhalation. In certain embodiments, a compound may be simply dissolvedor suspended in sterile water. Details of appropriate routes ofadministration and compositions suitable for same can be found in, forexample, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231,5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect. Generally, out of onehundred percent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association an active compound, such as a compound ofthe invention, with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound of the present inventionwith liquid carriers, or finely divided solid carriers, or both, andthen, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules (including sprinkle capsules and gelatin capsules),cachets, pills, tablets, lozenges (using a flavored basis, usuallysucrose and acacia or tragacanth), lyophile, powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouthwashes and the like, each containinga predetermined amount of a compound of the present invention as anactive ingredient. Compositions or compounds may also be administered asa bolus, electuary or paste.

To prepare solid dosage forms for oral administration capsules(including sprinkle capsules and gelatin capsules), tablets, pills,dragees, powders, granules and the like), the active ingredient is mixedwith one or more pharmaceutically acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, cetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; (10) complexing agents,such as, modified and unmodified cyclodextrins; and (11) coloringagents. In the case of capsules (including sprinkle capsules and gelatincapsules), tablets and pills, the pharmaceutical compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin, microcrystalline cellulose, orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (for example, sodium starch glycolate or cross-linkedsodium carboxymethyl cellulose), surface-active or dispersing agent.Molded tablets may be made by molding in a suitable machine a mixture ofthe powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions, such as dragees, capsules (including sprinkle capsules andgelatin capsules), pills and granules, may optionally be scored orprepared with coatings and shells, such as enteric coatings and othercoatings well known in the pharmaceutical-formulating art. They may alsobe formulated so as to provide slow or controlled release of the activeingredient therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may be sterilizedby, for example, filtration through a bacteria-retaining filter, or byincorporating sterilizing agents in the form of sterile solidcompositions that can be dissolved in sterile water, or some othersterile injectable medium immediately before use. These compositions mayalso optionally contain opacifying agents and may be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain portion of the gastrointestinal tract, optionally, in a delayedmanner. Examples of embedding compositions that can be used includepolymeric substances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms useful for oral administration includepharmaceutically acceptable emulsions, lyophiles for reconstitution,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, cyclodextrins and derivatives thereof, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof

Besides inert diluents, the compositions of the present invention canalso include adjuvants such as wetting agents, lubricants, emulsifyingand suspending agents such as sodium lauryl sulfate and magnesiumstearate, or sweetening, flavoring, coloring, perfuming, preservative,or anti-oxidant agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, orurethral administration may be presented as a suppository, which may beprepared by mixing one or more active compounds with one or moresuitable nonirritating excipients or carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the rectum or vaginal cavity and releasethe active compound.

Formulations of the pharmaceutical compositions for administration tothe mouth may be presented as a mouthwash, or an oral spray, or an oralointment.

Alternatively, or additionally, compositions can be formulated fordelivery via a catheter, stent, wire, or other intraluminal device.Delivery via such devices may be especially useful for delivery to thebladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also includepessaries, tampons, vaginal rings for sustained-release (e.g., polymericvaginal rings) creams, gels, pastes, foams or spray formulationscontaining such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration includepowders, sprays, ointments, pastes, creams, lotions, gels, solutions,patches and inhalants. The active compound may be mixed under sterileconditions with a pharmaceutically acceptable carrier, and with anypreservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The compounds described herein can be alternatively administered byaerosol. This is accomplished by preparing an aqueous aerosol, liposomalpreparation, or solid particles containing the composition. A nonaqueous(e.g., fluorocarbon propellant) suspension could be used. Sonicnebulizers are preferred because they minimize exposing the agent toshear, which can result in degradation of the compound.

Ordinarily, an aqueous aerosol is made by formulating an aqueoussolution or suspension of the agent together with conventionalpharmaceutically acceptable carriers and stabilizers. The carriers andstabilizers vary with the requirements of the particular composition,but typically include nonionic surfactants (Tweens, Pluronics, sorbitanesters, lecithin, Cremophors), pharmaceutically acceptable co-solventssuch as polyethylene glycol, innocuous proteins like serum albumin,oleic acid, amino acids such as glycine, buffers, salts, sugars, orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the active compound in theproper medium. Absorption enhancers can also be used to increase theflux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat.No. 6,583,124, the contents of which are incorporated herein byreference. If desired, liquid ophthalmic formulations have propertiessimilar to that of lacrimal fluids, aqueous humor or vitreous humor orare compatible with such fluids. A preferred route of administration islocal administration (e.g., topical administration, such as eye drops,or administration via an implant).

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, intravitreal and intrasternal injection andinfusion. Pharmaceutical compositions suitable for parenteraladministration comprise one or more active compounds in combination withone or more pharmaceutically acceptable sterile isotonic aqueous ornonaqueous solutions, dispersions, suspensions or emulsions, or sterilepowders which may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a ligand, drug, or other materialother than directly into the central nervous system, such that it entersthe patient's system and thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, metacresol, benzoic acid and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like into the compositions. Inaddition, prolonged absorption of the injectable pharmaceutical form maybe brought about by the inclusion of agents that delay absorption suchas aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous, intravitreal orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material having poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of agents may be given orally, parenterally, topically,or rectally. They are, of course, given by forms suitable for eachadministration route. For example, they are administered in tablets orcapsule form, by injection, inhalation, eye lotion, ointment,suppository, infusion; topically by lotion or ointment; and rectally bysuppositories. Oral administration is preferred.

For use in the methods of this invention, active compounds can be givenper se or as a pharmaceutical composition containing, for example, 0.1to 99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable orbiodegradable devices. Various slow release polymeric devices have beendeveloped and tested in vivo in recent years for the controlled deliveryof drugs, including proteinacious biopharmaceuticals. A variety ofbiocompatible polymers (including hydrogels), including bothbiodegradable and non-degradable polymers, can be used to form animplant for the sustained release of a compound at a particular targetsite.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally, and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds, whichmay be used in a suitable hydrated form, and/or the pharmaceuticalcompositions of the present invention, are formulated intopharmaceutically acceptable dosage forms by conventional methods knownto those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired therapeutic responsefor a particular patient, composition, and mode of administration,without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound or combination ofcompounds employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of metabolism orexcretion of the particular compound(s) being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with the particular compound(s) employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medical arts.In general, the compositions of this invention may be provided in anaqueous solution containing about 0.1-10% w/v of a compound disclosedherein, among other substances, for parenteral administration. Typicaldose ranges are from about 0.01 to about 50 mg/kg of body weight perday, given in 1 single or 2-4 divided doses. Each divided dose maycontain the same or different compounds of the invention.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the therapeutically effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the pharmaceutical composition orcompound at levels lower than that required in order to achieve thedesired therapeutic effect and gradually increase the dosage until thedesired effect is achieved. A “therapeutically effective amount” of acompound with respect to the subject method of treatment, refers to anamount of the compound(s) in a preparation which, when administered aspart of a desired dosage regimen (to a mammal, preferably a human)alleviates a symptom, ameliorates a condition, or slows the onset ofdisease conditions according to clinically acceptable standards for thedisorder or condition to be treated or the cosmetic purpose, e.g., at areasonable benefit/risk ratio applicable to any medical treatment. It isgenerally understood that the effective amount of the compound will varyaccording to the weight, sex, age, and medical history of the subject.Other factors which influence the effective amount may include, but arenot limited to, the severity of the patient's condition, the disorderbeing treated, the stability of the compound, and, if desired, anothertype of therapeutic agent being administered with the compound of theinvention. A larger total dose can be delivered by multipleadministrations of the agent. Methods to determine efficacy and dosageare known to those skilled in the art (Isselbacher et al. (1996)Harrison's Principles of Internal Medicine 13 ed., 1814-1882, hereinincorporated by reference).

In general, a suitable daily dose of an active compound used in thecompositions and methods of the invention will be that amount of thecompound that is the lowest dose effective to produce a therapeuticeffect or the maximally tolerated dose. Such an effective dose willgenerally depend upon the factors described above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. In certain embodiments of the presentinvention, the active compound may be administered two or three timesdaily. In preferred embodiments, the active compound will beadministered once daily.

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep; and poultry and pets in general.

In certain embodiments, compounds of the invention may be used alone orconjointly administered with another type of therapeutic agent. As usedherein, the phrase “conjoint administration” refers to any form ofadministration of two or more different therapeutic compounds such thatthe second compound is administered while the previously administeredtherapeutic compound is still effective in the body (e.g., the twocompounds are simultaneously effective in the patient, which may includesynergistic effects of the two compounds). For example, the differenttherapeutic compounds can be administered either in the same formulationor in a separate formulation, either concomitantly or sequentially. Incertain embodiments, the different therapeutic compounds can beadministered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72hours, or a week of one another. Thus, an individual who receives suchtreatment can benefit from a combined effect of different therapeuticcompounds.

This invention includes the use of pharmaceutically acceptable salts ofcompounds of the invention in the compositions and methods of thepresent invention. In certain embodiments, contemplated salts of theinvention include, but are not limited to, alkyl, dialkyl, trialkyl ortetra-alkyl ammonium salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, L-arginine,benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol,diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine,ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium,L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine,potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine,tromethamine, and zinc salts. In certain embodiments, contemplated saltsof the invention include, but are not limited to, Na, Ca, K, Mg, Zn, Cu,Fe or other metal salts.

The pharmaceutically acceptable acid addition salts can also exist asvarious solvates, such as with water, methanol, ethanol,dimethylformamide, dichloromethane, acetonitrile, acetone, ethylacetate, cyclopentyl methyl ether and the like. Mixtures of suchsolvates can also be prepared. The source of such solvate can be fromthe solvent of crystallization, inherent in the solvent of preparationor crystallization, or adventitious to such solvent.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1)water-soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfiteand the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),lecithin, propyl gallate, alpha-tocopherol, and the like; and (3)metal-chelating agents, such as citric acid, ethylenediamine tetraaceticacid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The invention now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

EXAMPLES Materials and Methods X-Ray Diffraction

As used herein, XRPD data can be collected using a PANalytical X'PertPro X-ray Diffractometer, scanning the samples between 3 and 35°2-theta. Material was loaded into a 96-well plate with Kapton or Mylarpolymer film as the base. The samples were then loaded into the plateholder of a PANalytical X'Pert Pro X-ray Diffractometer running intransmission mode and analyzed, using the following experimentalconditions:

-   -   Raw Data Origin: XRD measurement (*.XRDML)    -   Scan Axis: Gonio    -   Start Position [°2θ]: 3.0066    -   End Position [°2θ]: 34.9866    -   Step Size [°2θ]: 0.0130    -   Scan Step Time [s]: 18.8700    -   Scan Type: Continuous    -   PSD Mode: Scanning    -   PSD Length [°2θ]: 3.35    -   Offset [°2θ]: 0.0000    -   Divergence Slit Type: Fixed    -   Divergence Slit Size [°]: 1.0000    -   Specimen Length [mm]: 10.00    -   Measurement Temperature [°C]: 25.00    -   Anode Material:        Cu    -   K-Alpha1[Å]: 1.54060    -   K-Alpha2[Å]: 1.54443    -   K-Beta [Å]: 1.39225    -   K-A2/K-A1 Ratio: 0.50000    -   Generator Settings: 40 mA, 40 kV    -   Diffractometer Type: 0000000011154173    -   Diffractometer Number: 0    -   Goniometer Radius [mm]: 240.00    -   Dist. Focus-Diverg. Slit [mm]: 91.00    -   Incident Beam Monochromator: No    -   Spinning: No

Polarized Light Microscopy (PLM)

The presence of birefringence was determined using an Olympus BX50polarizing microscope, equipped with a Motic camera and image capturesoftware (Motic Images Plus 2.0). Material was dispersed in silicone oilprior to image capture. All images were recorded using the 20×objective, unless otherwise stated.

Thermogravimetric/Differential Thermal Analysis (TG/DTA)

Approximately 5 mg of material was weighed into an open aluminum pan andloaded into a Seiko TGA6200 simultaneous thermogravimetric/differentialthermal analyzer (TG/DTA) and held at room temperature. The sample wasthen heated at a rate of 10° C./min from 20° C. to 300° C. during whichtime the change in sample weight was recorded along with anydifferential thermal events (DTA). Nitrogen was used as the purge gas,at a flow rate of 300 cm3/min.

Differential Scanning Calorimetry (DSC)

Approximately 5 mg of material was weighed into an aluminum DSC pan andsealed nonhermetically with a pierced aluminum lid. The sample pan wasthen loaded into a Seiko DSC6200 (equipped with a cooler) and held at20° C. Once a stable heat-flow response was obtained, the sample andreference were heated to ca. 190° C. at a scan rate of 10° C./min andthe resulting heat flow response monitored. Nitrogen was used as thepurge gas, at a flow rate of 50 cm3/min.

Karl Fischer Coulometric Titration (KF)

Approximately 10-15 mg of solid material was accurately weighed into aglass weigh-boat. The solid was then manually introduced into thetitration cell of a Mettler Toledo C30 Compact Titrator. The weigh-boatwas back-weighed after the addition of the solid and the weight of theadded solid entered on the instrument. The titration was initiated oncethe sample had fully dissolved in the cell. The water content wascalculated automatically by the instrument as a percentage and the dataprinted.

¹H Nuclear Magnetic Resonance Spectroscopy (1H NMR)

¹H-NMR spectroscopic experiments were performed on a Bruker AV500(frequency: 500 MHz). Experiments were performed in D₂O and each samplewas prepared to ca. 10 mM concentration.

Dynamic Vapor Sorption (DVS)

Approximately 10 mg of sample was placed into a mesh vapor sorptionbalance pan and loaded into a DVS-1 dynamic vapor sorption balance bySurface Measurement Systems. The sample was subjected to a rampingprofile from 40-90% relative humidity (RH) at 10% increments,maintaining the sample at each step until a stable weight had beenachieved (99.5% step completion). After completion of the sorptioncycle, the sample was dried using the same procedure to 0% RH and then asecond sorption cycle back to 40% RH. The weight changes during thesorption/desorption cycles were plotted, allowing the hygroscopic natureof the sample to be determined. XRPD analysis was then carried out onthe remaining solid.

Gravimetric Vapor Sorption (GVS)

Approximately 10-20 mg of sample was placed into a mesh vapor sorptionbalance pan and loaded into an IGASorp Moisture Sorption Analyzerbalance by Hiden Analytical. The sample was subjected to a rampingprofile from 5-90% relative humidity (RH) at 10% increments, maintainingthe sample at each step until a stable weight had been achieved (98%step completion). After completion of the sorption cycle, the sample wasdried using the same procedure to 0% RH, and finally taken back to 40%RH. The weight changes during the sorption/desorption cycles wereplotted, allowing the hygroscopic nature of the sample to be determined.XRPD analysis was then carried out on the remaining solid.

High Performance Liquid Chromatography-Ultraviolet Detection (HPLC-UV)

Column: Aeris Peptide C18 3.6 Pm 250×4.6 mm column

-   -   Mobile Phase A: 0.1% TFA in H₂O    -   Mobile Phase B: 0.1% TFA in acetonitrile    -   Diluent: H₂O: acetonitrile (90:10 v/v)    -   Flow Rate: 1.0 mL/min    -   Runtime: 36 minutes    -   Column Temperature: 40° C.    -   Autosampler Temperature: 5° C.    -   Injection Volume: 30 μL    -   Detection: 220 nm    -   Sample Concentration: 0.4 mg/mL    -   Gradient program:

Time/min Solvent B (%) 0.00 2 25.00 40 25.10 100 26.90 100 27.00 2 36.002

Ion Chromatography (IC)

Column: Dionex IonPac AS14A-5Pm, 3×150 mm

-   -   Guard Column: Dionex IonPac AG14A-5Pm, 3×30 mm    -   Mobile Phase: 8 mM Na₂CO₃/1 mM NaHCO₃    -   Diluent: Purified water    -   Flow Rate: 0.5 mL/min    -   Runtime: 15 minutes    -   Detector suppression: 50 mA, water regenerant as required    -   Column Temperature: 30° C.    -   Injection Volume: 25μL (sample volume may be adjusted as        required)    -   Sample Concentration: 0.4 mg/mL in water

Stability Testing

Approximately 30 mg of the tosylate and fumarate salts were subjected to7-day stability testing under the following conditions:

-   -   40° C./75% RH    -   80° C.    -   Ambient temperature and light        After 7 days under the stated conditions, XRPD and HPLC analysis        was carried out on the resultant solid material.

Salt Disproportionation Studies

Salt disproportionation studies were carried out on the tosylate andfumarate salts using the following procedure:

-   -   Approximately 30 mg of salt was slurried in 300 μL of deionized        water.    -   Slurries were stirred at 20° C. for 30 min then measured pH        before leaving to stir overnight.    -   After stirring slurries at 20° C. for 20 h, pH was re-measured.    -   Solid material isolated by centrifugation and analyzed by XRPD.

Stability Testing

Approximately 30 mg of the tosylate and fumarate salts were subjected to7-day stability testing under the following conditions:

-   -   40° C./75% RH    -   80° C.    -   Ambient temperature and light    -   After 7 days under the stated conditions, XRPD and HPLC analysis        was carried out on the resultant solid material.

Hydration Studies

Hydration studies were carried out on the tosylate and fumarate saltsusing the following procedure:

-   -   Approximately 15-40 mg of salt was slurried in 200-500 μL of        IPA/water, adding the solvent in 100 μL aliquots until a mobile        slurry was achieved.    -   3 different water activities (aw), determined using the Wilson        equation, were used: 0.368 (0.2% water), 0.608 (7.3% water) and        0.911 (67.9% water). IPA was dried over 3 A molecular sieves        before use.    -   Slurries were stirred at 20° C. for 25 h then solid material was        isolated by centrifugation and analyzed by XRPD.

TABLE A Experimental Details for Hydration Studies Salt a_(W) Mass ofSalt (mg) Solvent Volume (μL) Tosylate 0.368 25 500 0.608 25 500 0.91140 200 Fumarate 0.368 15 400 0.608 25 400 0.911 41 500

Thermodynamic Solubility Studies

Thermodynamic solubility studies at 3 different pH values were carriedout on the tosylate and fumarate salts using the following procedure:

-   -   Approximately 30 mg of salt was slurried in the appropriate        buffer solution, adding the solvent in 100 μL aliquots until a        mobile slurry was achieved.    -   3 different buffers prepared: pH 1.2, pH 4.5 and pH 6.8.    -   Stirred at 20° C. then checked pH and adjusted if necessary.    -   Stirred at 20° C. for 1.5 h then added more solid, if required,        to create slurries. pH checked again and adjusted if necessary.    -   Stirred at 20° C. for 22 h then checked pH and readjusted to        required values and left for a further 2 h so that reactions        stirred at 20° C. for 24 h total.    -   Solid material isolated by centrifugation and analyzed by XRPD.    -   Solutions analyzed by HPLC for concentration.

pH 1.2 Buffer Preparation:

25 mL of 0.2 M potassium chloride solution and 42.50 mL of 0.2 Mhydrochloric acid solution were diluted to 100 mL using deionized water.The pH was adjusted as required, using either potassium chloride orhydrochloric acid solution.

pH 4.5 Buffer Preparation:

25 mL of 0.2 M potassium hydrogen phthalate solution and 2.50 mL of 0.2M sodium hydroxide solution were diluted to 100 mL using deionizedwater. The pH was adjusted as required, using either potassium hydrogenphthalate or sodium hydroxide solution.

pH 6.8 Buffer Preparation:

25 mL of 0.2 M potassium phosphate monobasic solution and 11.20 mL of0.2 M sodium hydroxide solution were diluted to 100 mL using deionizedwater. The pH was adjusted as required, using either potassium phosphatemonobasic or sodium hydroxide solution.

Example 1. Primary Salt Screen

Six solvent systems were selected for the primary salt screen: methanol,2-propanol, acetone:water (90:10 v/v), dichloromethane, anisole andacetonitrile:ethylene glycol (90:10 v/v). Based on the calculated (andmeasured) pKa values for the received material, 24 counterions wereselected for the primary salt screen (Table B), to be carried outalongside 6 blank experiments using the received acetate salt.

TABLE B Selected Counterions for Primary Salt Screen pKa No. Acid Class1 2 3 LogP MW 1 Hydrochloric acid 1 −6.10 36.46 2 Sulfuric 1 −3.00 1.92−1.03 98.08 3 Cholesteryl sulfate −3.00 4.45 466.72 (sodium 4p-Toluenesulfonic 2 −1.34 0.93 190.22 acid 5 Methanesulfonic 2 −1.20−1.89 96.10 acid 6 Naphthalene-2- sulfonic acid 7 Benzenesulfonic 2 0.700.47 158.18 acid 8 Oxalic 2 1.27 4.27 −1.19 90.04 9 Maleic 1 1.92 6.23−0.01 116.07 10 Phosphoric acid 1 1.96 7.12 12.32 −2.15 98.00 11Ethanesulfonic acid 2 2.05 −1.36 110.13 12 L-Glutamic acid 1 2.19 4.25−1.43 147.13 13 1-Hydroxy-2- 2 2.70 13.50 3.29 188.17 naphthoic 14L-Tartaric acid 1 3.02 4.36 −1.43 150.09 15 Fumaric 1 3.03 4.38 −0.01116.07 16 Citric 1 3.13 4.76 6.40 −1.72 192.12 17 D-Glucuronic acid 13.18 −1.49 194.14 18 L-Malic 1 3.46 5.10 −1.26 134.09 19 Hippuric acid 13.55 0.31 179.17 20 Benzoic 2 4.19 1.89 122.12 21 Succinic acid 1 4.215.64 −0.59 118.09 22 Adipic 1 4.44 5.44 0.08 146.14 23 Deoxycholic acid4.76 3.8 392.57 24 Lauric 1 4.90 4.6 200.32

The primary salt screen was carried out on 35 mg scale in a glovebagunder nitrogen using >3 equivalents of the counterions in theappropriate solvent. The contents of the vials were temperature cycledfrom 30 to 5° C. Any solids were isolated and analyzed by XRFD.

-   -   Approximately 35 mg of received material was weighed into each        vial, in a glovebag under nitrogen. If amorphous material or        counterion isolated, material was returned to vial and solids        re-dissolved through addition of an appropriate solvent. Further        temperature cycling was then employed, followed by anti-solvent        addition and evaporation if required. Solids, if present, were        isolated by centrifugation and analyzed by XRPD. Crystalline        material was further analyzed by PLM, TG/DTA and subjected to        stability testing for 72 hours at 40° C./75% RH, with        post-stability XRPD and HPLC analysis.

TABLE C Summary of Crystalline Hits from Primary Salt Screen Same Mor-XRPD, Counterion/ Crystallinity phology post- Purity Solvent by XRPD byPLM stability by HPLC p-TsOH, MeOH P1, moderate unclear yes 80.6 p-TsOH,IPA P2, good needles no, P1 98.9 p-TsOH, MeCN/EG P1, good plates/rods ndnd MSA, MeOH P1, good unclear new form 91.1 MSA, IPA P1, good unclearnew form 97.2 MSA, acetone/water P2, good unclear new form 99.2 MSA, DCMP1, good unclear nd nd MSA, anisole P1, good unclear nd nd Oxalic acid,MeOH P1, moderate unclear nd nd Oxalic acid, IPA P1, good needlesamorphous 99.0 Oxalic acid, P2, good unclear amorphous 97.1acetone/water ESA, IPA P1, good unclear new form 95.8 ESA, DCM P2,moderate unclear nd nd ESA, anisole P2, good unclear new form 90.5Fumaric acid, IPA P1, good rods/ yes (less 99.8 needles crystalline)Fumaric acid, P2, moderate unclear nd nd acetone/water Benzoic acid, IPAP1, moderate unclear nd nd Succinic acid, P1, moderate unclear amorphous98.0 acetone/water Cholesteryl sulfate, P1, moderate unclear poorly ndMeOH crystalline (insoluble) Cholesteryl sulfate, P2, moderate unclearnew form nd MeCN/EG (insoluble) P1 = Pattern 1; P2 = Pattern 2

Example 2. General Procedure for the Preparation of Crystalline Forms

MTP-131 was charged to a vial in a glovebag under nitrogen and slurriedin the appropriate solvent at 20° C.

solution of the counterion was charged was added dropwise to the vialcontaining the material (homogeneity solvent dependent). The slurry wasstirred at 27±7° C. to achieve dissolution. In some cases, a co-solventsuch as water was added incremental to achieve dissolution. The solutionwas temperature cycled between 40 and 0° C. The material was isolatedthrough filtration using a Buchner funnel, rinsed with the appropriatesolvent and then dried under vacuum at ambient temperature for 58 hbefore characterization. A portion of the material was further dried at40° C. for ca. 48 h and then analyzed by TG/DTA.

Example 3. Small-Scale Tosylate Salt Synthesis

-   -   The tosylate salt (500 mg scale) was prepared using IPA with        water as the co-solvent to achieve dissolution.    -   Powder X-ray diffraction pattern and XRPD peaks with relative        intensities of the crystalline tosylate form thus prepared are        shown in FIG. 9 and Table 3, respectively.

Example 4. Further Small-Scale Fumarate Salt Synthesis

-   -   The fumarate salt was prepared on 35mg scale.    -   Different ratios of fumaric acid were used as indicated in Table        D.    -   For experiments yielding solid material were isolated by        centrifugation and analyzed by XRPD.

TABLE D Experimental Details for further Small-Scale Fumarate Reactions.Eq. Temperature Initial Fumaric Cycling Solvent Acid Additional Solvent(Volume) (h) 1 IPA 3.1 Water, 100 μL 92 2 IPA:water 3.1 IPA:water(7.55:1 v/v), 92 (7.55:1 v/v) 250 μL 3 IPA 3.1 Water, 300 μL; IPA, 150μL 92 4 IPA 4.6 Water, 250 μL 16 5 Acetone 4.6 Water, 250 μL 16 6Acetonitrile 4.6 Water, 250 μL 16 7 1-Butanol 4.6 Water, 400 μL;1-butanol, 30 200 μL; IPA, 450 μL 8 1-Propanol 4.6 Water, 250 μL 16

After stirring at 20° C. for 2.5 h, slurries were fully dissolvedthrough the addition of water, with further organic solvent added ifseparation occurred (Reactions 5 and 7). After temperature cyclingovernight, solid material was isolated from Reactions 4-6 and 8. Pattern3 was isolated from Reactions 1-4 and 5, with new patterns isolated fromReactions 6 and 8. After adding additional IPA to Reaction 7 andtemperature cycling overnight, solid material corresponding to anothernew pattern was isolated.

Example 5. Preparation of Fumarate Pattern 3

-   -   The fumarate salt (500 mg scale) was prepared using IPA with        water as the co-solvent to achieve dissolution.    -   After 1 h stirring at ambient temperature, mixing was poor as        the material had precipitated to give a thick slurry. Aliquots        of IPA were added until solvent composition was IPA-water        (˜4:1).    -   Stirred at ambient temperature (ca. 23° C.) for 17 h, then        isolated through filtration using a Buchner funnel, rinsed with        IPA and then dried under vacuum at ambient temperature for 22.5        h before characterization.

Example 6. Tosylate Salt

The following observations and results were made during characterizationof the tosylate salt:

-   -   Tosylate Pattern 1 was crystalline by XRPD analysis, with no        clearly defined morphology observed in the PLM analysis of the        sample from methanol. Both plates and rods were observed in the        PLM analysis of the sample from acetonitrile:ethylene glycol        (90:10 v/v) and all samples were birefringent.    -   Pattern 1 is potentially a hydrated form, with loss of ca. 1.7%        in the TGA from the outset to ca. 90° C. likely due to loss of        water. This was followed by a further weight loss of 0.3%        (90-200° C.) before the onset of decomposition.    -   Pattern 1 showed a small endothermic event in the DTA at ca.        70.5° C., associated with the initial weight loss. A further        endotherm was observed at onset ca. 203.8° C. (peak at ca.        214.8° C.).    -   Tosylate Pattern 2 was crystalline by XRPD analysis, with        birefringence and a needle-like morphology observed in the PLM        analysis of the sample from IPA.    -   Pattern 2 is also potentially a hydrated form, with loss of ca.        1.2% in the TGA from the outset to ca. 80° C. likely due to loss        of water. This is followed by a further weight loss of 0.1%        (80-190° C.) before the onset of decomposition.    -   Pattern 2 showed an endothermic event in the DTA at onset ca.        217.1° C. (peak at ca. 226.8° C.).    -   XRPD analysis of samples after stability testing at 40° C./75%        RH indicated that Pattern 1 (from methanol) improved in        crystallinity after stability, while Pattern 2 (from IPA)        converted to Pattern 1.    -   HPLC analysis of samples after stability testing at 40° C./75%        RH indicated that Pattern 1    -   (from methanol) had a purity of 80.6%, while Pattern 1 (from        IPA) had a purity of 98.9%.

Example 7. Mesylate Salt

The following observations and results were made during characterizationof the mesylate salt:

-   -   Mesylate Pattern 1 was crystalline by XRPD analysis and        birefringent by PLM analysis, with no clearly defined morphology        observed in the samples from methanol, IPA, DCM or anisole. The        particles were observed to be very small.    -   Pattern 1 is potentially a hydrate or solvate, with loss of ca.        3.8% in the TGA from the outset to ca. 110° C. This is followed        by a further weight loss of 1.0% (110-220° C.) before the onset        of decomposition. Further confirmation as to the nature of this        solid form is required.    -   Pattern 1 showed a small endothermic event in the DTA at ca.        84.8° C., associated with the initial solvent loss. A further        endotherm was observed at onset ca. 186.4° C. (peak at ca.        196.4° C.).    -   Further TG/DT analysis of Pattern 1 was carried out on samples        isolated from IPA and DCM. Pattern 1 from IPA is potentially a        hydrate or solvate, with loss of ca. 1.3% in the TGA from the        outset to ca. 100° C. This is followed by a further weight loss        of 2.0% (100-220° C.) before the onset of decomposition. Pattern        1 from IPA showed small endothermic events in the DTA at ca.        77.5° C. and ca. 164.9° C., associated with these solvent/water        losses. A further endotherm was observed at onset ca. 191.1° C.        (peak at ca. 194.9° C.).    -   Pattern 1 from DCM is potentially a hydrate or solvate, with        loss of ca. 4.0% in the TGA from the outset to ca. 160° C. This        is followed by a further weight loss of 1.0% (160-220° C.)        before the onset of decomposition. Pattern 1 from DCM showed a        small endothermic event in the DTA at ca. 178.0° C., associated        with solvent loss. A further endotherm was observed at onset ca.        188.4° C. (peak at ca. 196.1° C.).    -   Mesylate Pattern 2 was crystalline by XRPD analysis and        birefringent by PLM analysis, with no clearly defined morphology        observed in the sample from acetone:water (90:10 v/v).    -   Pattern 2 is potentially a solvate/hydrate, with loss of ca.        5.3% in the TGA from the outset to ca. 120° C. This is followed        by a further weight loss of 2.1% (120-175° C.) before the onset        of decomposition. Further confirmation as to the nature of this        solid form is required.    -   Pattern 2 showed a small endothermic event in the DTA at        62.1° C. and a further endothermic event at onset ca. 129.2° C.        (peak at ca. 136.6° C.).    -   XRPD analysis of samples after stability testing at 40° C./75%        RH indicated that both Pattern 1 (from methanol and IPA) and        Pattern 2 (from acetone:water 90:10 v/v) lost crystallinity and        converted to a different pattern after stability. A broad,        poorly crystalline pattern was obtained in each case.    -   HPLC analysis of samples after stability testing at 40° C./75%        RH indicated that the sample from methanol had a purity of        91.1%, the sample from IPA had a purity of 97.2% and the sample        from acetone:water 90:10 v/v had a purity of 99.2%.

Example 8. Oxalate Salt

The following observations and results were made during characterizationof the oxalate salt:

-   -   Oxalate Pattern 1 was crystalline by XRPD analysis and        birefringent by PLM analysis. No clearly defined morphology was        observed in the sample obtained from methanol, but needles were        observed from IPA.    -   Pattern 1 is potentially a solvate/hydrate, with loss of ca.        7.7% in the TGA from the outset to ca. 90° C., followed by a        further weight loss of 6.6% (90-160° C.) before the onset of        decomposition.    -   Pattern 1 showed endothermic events in the DTA at onset ca.        53.0° C. (peak at ca. 69.5° C.), at onset ca. 134.3° C. (peak at        ca. 137.6° C.) and at onset ca. 168.0° C. (peak at ca. 178.5°        C.).    -   Oxalate Pattern 2 was crystalline by XRPD analysis and        birefringent by PLM analysis, with no clearly defined morphology        observed in the sample obtained from acetone:water (90:10 v/v).    -   Pattern 2 is potentially a solvate/hydrate, with loss of ca.        7.0% in the TGA from the outset to ca. 140° C. Further weight        loss is likely associated with decomposition.    -   Pattern 2 showed a broad endothermic event in the DTA at onset        ca. 185.4° C. (peak at ca.    -   203.5° C.), likely associated with decomposition.    -   XRPD analysis of samples after stability testing at 40° C./75%        RH indicated that both Pattern 1 (from IPA) and Pattern 2 (from        acetone:water (90:10 v/v)) lost all crystallinity and converted        to amorphous material after stability    -   HPLC analysis of samples after stability testing at 40° C./75%        RH indicated that the sample from IPA had a purity of 99.0% and        the sample from acetone:water (90:10 v/v) had a purity of 97.1%.

Example 9. Esylate Salt

The following observations and results were made during characterizationof the esylate salt:

-   -   Esylate Pattern 1 was crystalline by XRPD analysis and        birefringent by PLM analysis. No clearly defined morphology was        observed in the sample from IPA; particles were small and there        was some agglomeration observed.    -   Pattern 1 is potentially a hydrate or anhydrous form, with loss        of ca. 3.0% in the TGA from the outset to ca. 90° C., followed        by a further weight loss of 0.4% (90-200° C.) before the onset        of decomposition. Further analysis would be required in order to        establish the exact nature of the form.    -   Pattern 1 showed endothermic events in the DTA at onset ca.        78.6° C. (peak at ca. 80.5° C.), and at onset ca. 158.6° C.        (peak at ca. 169.7° C.).    -   Esylate Pattern 2 was crystalline by XRPD analysis and        birefringent by PLM analysis, with no clearly defined morphology        observed in the samples obtained from dichloromethane or        anisole.    -   Pattern 2 is potentially a hydrate or anhydrous form, with loss        of ca. 3.4% in the TGA from the outset to ca. 90° C., followed        by further weight losses of 0.2% (90-145° C.) and 0.6% (145-210°        C.) before the onset of decomposition. Further analysis would be        required in order to establish the exact nature of the form.    -   Pattern 2 showed a broad endothermic event in the DTA at onset        ca. 43.0° C. (peak at ca. 61.6° C.) and further, overlapped        endothermic events at onset ca. 154.3° C. (peaks at ca.        168.8° C. and at 181.8° C.).    -   XRPD analysis of samples after stability testing at 40° C./75%        RH indicated that both Pattern 1 (from IPA) and Pattern 2 (from        anisole) converted to a new pattern after stability. The sample        from IPA lost crystallinity in this conversion, while the sample        from anisole improved in crystallinity.    -   HPLC analysis of samples after stability testing at 40° C./75%        RH indicated that the sample from IPA had a purity of 95.8% and        the sample from anisole had a purity of 90.5%.

Example 10. Fumarate Salt

The following observations and results were made during characterizationof the fumarate salt:

-   -   Fumarate Pattern 1 was crystalline by XRPD analysis and        birefringent by PLM analysis. Both rod-like and needle-like        morphology was observed in the sample from IPA.    -   Pattern 1 is potentially a solvate/hydrate, with loss of ca.        4.5% in the TGA from the outset to ca. 100° C. This is followed        by a further weight loss of 2.0% (100-160° C.) before the onset        of decomposition.    -   Pattern 1 showed endothermic events in the DTA at onset ca.        132.6° C. (peak at ca. 140.8° C.), and at onset ca. 183.1° C.        (peak at ca. 198.5° C.).    -   Fumarate Pattern 2 was crystalline by XRPD analysis and        birefringent by PLM analysis, with no clearly defined morphology        observed in the sample obtained from acetone:water (90:10 v/v).    -   Pattern 2 is potentially a solvate/hydrate, with loss of ca.        2.6% in the TGA from the outset to ca. 50° C. This is followed        by a further weight loss of 5.1% (50-150° C.) before the onset        of decomposition.    -   Pattern 2 showed endothermic events in the DTA at onset ca.        137.3° C. (peak at ca. 147.1° C.) and at onset ca. 188.2° C.        (peak at ca. 207.8° C.).    -   XRPD analysis of the sample after stability testing at 40°        C./75% RH indicated that Pattern 1 (from IPA) lost some        crystallinity but retained the same form after stability. Not        enough material remained of Pattern 2 to carry out stability        testing.    -   HPLC analysis of the sample after stability testing at 40°        C./75% RH indicated that the sample from IPA had a purity of        99.8%.

Example 11. Benzoate Salt

The following observations and results were made during characterizationof the benzoate salt:

-   -   Benzoate Pattern 1 was crystalline by XRPD analysis and        birefringent by PLM analysis, with no clearly defined morphology        observed in the sample from IPA.    -   Pattern 1 is potentially a solvate/hydrate, with loss of ca.        5.8% in the TGA from the outset to ca. 130° C. This is followed        by further weight losses of 2.4% (130-180° C.) and 2.7%        (180-240° C.) before the onset of decomposition.    -   Pattern 1 showed no events in the DTA until an endothermic event        at ca. 245.5° C., likely associated with decomposition.    -   Not enough material remained of Pattern 1 to carry out stability        testing.

Example 12. Succinate Salt

The following observations and results were made during characterizationof the succinate salt:

-   -   Succinate Pattern 1 was crystalline by XRPD analysis and        birefringent by PLM analysis, with no clearly defined morphology        observed in the sample from acetone:water (90:10 v/v).    -   Pattern 1 is potentially a solvate/hydrate, with loss of ca.        8.3% in the TGA from the outset to ca. 145° C. This is followed        by a further weight loss of 7.9% (145-240° C.), associated with        the onset of decomposition.    -   Pattern 1 showed an endothermic event in the DTA at onset ca.        64.8° C. (peak at ca. 75.0° C.), with a small exothermic event        at ca. 140.3° C. A further endothermic event at onset ca.        178.6° C. (peak at ca. 199.7° C.) is associated with the onset        of decomposition.    -   XRPD analysis of the sample after stability testing at 40°        C./75% RH indicated that Pattern 1 (from acetone:water (90:10        v/v)) lost crystallinity and became amorphous after stability.    -   HPLC analysis of the sample after stability testing at 40°        C./75% RH indicated that the sample from acetone:water(90:10        v/v) had a purity of 98.0%.

Example 13. Cholesteryl Sulfate Salt

The following observations and results were made during characterizationof the cholesteryl sulfate salt:

-   -   Cholesteryl sulfate Pattern 1 was crystalline by XRPD analysis        and birefringent by PLM analysis with no clearly defined        morphology observed in the sample from methanol.    -   Pattern 1 is potentially a hydrate or anhydrous form, with loss        of ca. 2.9% in the TGA from the outset to ca. 200° C. Further        weight loss is associated with the onset of decomposition.        Further analysis would be required in order to establish the        exact nature of the form.    -   Pattern 1 showed a small endothermic event in the DTA at        105.1° C. and a further endothermic event at onset ca. 204.0° C.        (peak at ca. 215.3° C.).    -   Cholesteryl sulfate Pattern 2 was crystalline by XRPD analysis        and birefringent by PLM analysis, with no clearly defined        morphology observed in the sample obtained from        acetonitrile:ethylene glycol (90:10 v/v).    -   Pattern 2 is potentially a solvate/hydrate, with loss of ca.        1.5% in the TGA from the outset to ca. 90° C. followed by a        further weight loss of 8.1% (90-150° C.) before the onset of        decomposition.    -   Pattern 2 showed endothermic events in the DTA at onset ca.        104.5° C. (peak at ca. 118.4° C.) and at ca. 205.1° C.    -   XRPD analysis of the sample after stability testing at 40°        C./75% RH indicated that Pattern 1 (from methanol) lost        crystallinity after stability, with only traces of the input        pattern visible in the diffractogram. Pattern 2 (from        acetonitrile:ethylene glycol (90:10 v/v)) converted to a        different pattern after stability.    -   HPLC analysis of the samples after stability testing at 40°        C./75% RH was unsuccessful due to the low solubility of the        samples, even when DMSO was used as the diluent.

Example 14. Preparation of Tosylate Pattern 1

The following observations and results were obtained during preparationand characterization of the tosylate salt in the secondary salt screen:

-   -   IPA was used as the reaction solvent in the secondary salt        screen, with the addition of water to favor conversion of        Pattern 2 to Pattern 1.    -   After dissolving the slurry with water, a large amount of        precipitate formed after stirring for 2 h at 25° C. XRPD        analysis of a sample of this solid indicated that it was the        desired Pattern 1 material.    -   XRPD analysis of a sample of the solid after diluting with IPA        and temperature cycling for a further 64 h indicated that it was        still the desired Pattern 1 material.    -   After isolation and drying at ambient temperature for 58 h, 0.64        g of material was obtained (88% yield, based on 3 eq. of        tosylate).    -   The dried material was observed to remain Pattern 1 by XRPD        analysis and was slightly birefringent by PLM analysis, with a        rod-like morphology.    -   TG analysis after 24 h drying at ambient temperature showed a        weight loss of ca. 1.1% from the outset up to ca. 90° C. No        further weight loss was observed prior to the onset of        decomposition.    -   DTA after 24 h drying at ambient temperature showed endothermic        events at ca. 60.4° C. and at ca. 230.7° C., likely due to        melting of the material.    -   TG analysis after 42 h drying at ambient temperature showed a        weight loss of ca. 1.4% from the outset up to ca. 90° C. No        further weight loss was observed prior to the onset of        decomposition. (Note: 1 molar equivalent of water would        correspond to ca. 1.55 wt %)    -   DTA after 42 h drying at ambient temperature showed an        endothermic event at ca. 66.8° C. and at onset ca. 222.9° C.        (peak at 231.1° C.), likely due to melting of the material.    -   TG analysis after 58 h drying at ambient temperature showed a        weight loss of ca. 1.3% from the outset up to ca. 90° C. No        further weight loss was observed prior to the onset of        decomposition.    -   DTA after 58 h drying at ambient temperature showed an        endothermic event at ca. 65.4° C. and at onset ca. 224.8° C.        (peak at 230.2° C.), likely due to melting of the material.    -   TG analysis after 58 h drying at ambient temperature and 48 h        drying at 40° C. showed a weight loss of ca. 1.3% from the        outset up to ca. 90° C. No further weight loss was observed        prior to the onset of decomposition.    -   DTA after 58 h drying at ambient temperature and 48 h drying at        40° C. showed an endothermic event at ca. 64.7° C. and at onset        ca. 223.7° C. (peak at 230.5° C.), likely due to melting of the        material.    -   DSC showed an endothermic event at onset ca. 108.3° C. (peak at        ca. 138.6° C.), likely due to water loss, and a further        endothermic event at onset ca. 224.3° C. (peak at ca. 232.6°        C.), likely due to melting of the material.    -   The 1H NMR spectrum of the received material was consistent with        a tosylate salt and suggested ca. 3 eq. of tosylate present.    -   DVS analysis of the tosylate salt showed it to be slightly        hygroscopic, with a change in mass of ca. 1.3% between 20-90%        RH.    -   Post-DVS XRPD analysis of the tosylate salt showed it remained        Pattern 1 after the DVS experiment. The physical appearance of        the post-DVS material was unchanged.    -   KF analysis of the tosylate salt gave a water content of ca.        2.1% (average of 3 samples run).    -   By HPLC analysis, the purity of the tosylate salt was 99.8%.

Example 15. Preparation of Fumarate Pattern 3

The following observations and results were obtained during preparationand characterization of the fumarate salt, Pattern 3 in the secondarysalt screen:

-   -   Using Procedure 2, a large amount of precipitate formed after        dissolving the slurry with water and temperature cycling for        14 h. XRPD analysis of a sample of this solid indicated that it        was mostly amorphous.    -   XRPD analysis of a sample after recrystallizing using water,        seeding with Pattern 1 material and temperature cycling for a        further 19 h indicated that it was poorly crystalline Pattern 3.    -   XRPD analysis of samples after recrystallizing using water/IPA        and stirring at ambient temperature for ca. 24 h indicated        crystalline Pattern 3.    -   After isolation and drying at ambient temperature for 19 h, 0.37        g of material was obtained (59% yield, based on 3 eq. of        fumarate).    -   The dried material was observed to have a different pattern to        the isolated material by XRPD analysis, likely due to loss of        solvent/water upon drying. This pattern was designated Pattern        4.    -   The fumarate salt was birefringent by PLM analysis, with a        needle-like morphology.    -   TG analysis after 19 h drying showed a weight loss of ca. 5.2%        from the outset up to ca. 100° C., followed by weight losses of        ca. 0.5% between 100-140° C. and ca. 2.6% between 140-160° C.,        prior to the onset of decomposition. (Note: 3 molar equivalents        of water would correspond to ca. 5.78 wt%).    -   DTA showed an endothermic event at ca. 63.8° C. and at onset ca.        147.3° C. (peak at 151.2° C.), likely due to loss of water.    -   DSC showed several overlapping endotherms at onset ca. 64.7° C.        (peaks at ca. 81.3° C., 96.3° C. and 117.6° C.). A further        endotherm was observed at onset ca. 144.7° C. (peak at ca.        153.4° C.).    -   The 1H NMR spectrum of the isolated material was consistent with        a fumarate salt and suggested ca. 2.2 eq. of fumarate present.        IPA was also visible in the spectrum.    -   DVS analysis of the fumarate salt showed it to be hygroscopic,        with a change in mass of ca. 11.5% between 20-90% RH.    -   Post-DVS XRPD analysis of the fumarate salt showed it remained        Pattern 4 after the DVS experiment, although loss of        crystallinity was observed. The physical appearance of the        post-DVS material was unchanged.    -   KF analysis of the fumarate salt gave a water content of ca.        7.5% (average of 3 samples run). As the TGA shows mass loss of        ca. 8.3% before decomposition this loss is likely mostly water,        with some IPA also present.    -   By HPLC analysis, the purity of the fumarate salt was 99.9%.

Procedure 3:

-   -   Using Procedure 3, a large amount of precipitate formed after        dissolving the slurry with water and stirring at ambient        temperature (ca. 23° C.) for 1 h. XRPD analysis of a sample of        this solid indicated that it was poorly crystalline Pattern 3.    -   After recrystallizing using water/IPA and stirring at ambient        temperature (ca. 23° C.) for 17 h, XRPD analysis of a sample        indicated that it was crystalline Pattern 3.    -   After isolation and drying at ambient temperature for 22.5 h,        0.26 g of material was obtained (42% yield, based on 3 eq. of        fumarate).    -   XRPD analysis of the dried material indicated that it was        Pattern 4. This batch of material was used in the solubility and        hydration studies.

Example 16. Stability Testing

The scaled-up tosylate and fumarate salts were subjected to 7-daystability testing at 40° C./75% RH, 80° C. and ambient temperature andlight. The following observations and results were obtained during thesestability tests:

-   -   Post-stability XRPD analysis of the tosylate samples indicated        that input Pattern 1 was unchanged after stability testing.    -   Post-stability HPLC analysis of the tosylate samples indicated        that there was a slight decrease (<0.5%) in purity after        stability testing at 80° C. and ambient light/temperature. A        decrease in purity of ca. 1.3% after stability testing at 40°        C./75% RH was observed.    -   Post-stability XRPD analysis of the fumarate samples indicated        that input Pattern 4 was unchanged at lower temperatures, with        no significant crystallinity loss at 40° C./75% RH, or under        ambient conditions. At 80° C., a loss of crystallinity was        observed.    -   Post-stability HPLC analysis of the fumarate samples indicated        that there was a slight decrease (<0.5%) in purity after        stability testing at ambient light/temperature and a decrease in        purity of ca. 2.4% after stability testing at 40° C./75% RH.        However, a significant decrease in purity of ca. 17% was        observed after stability testing at 80° C.

TABLE E 7 Day Stability Data for Tosylate and Fumarate Salts Purity byHPLC Salt Stability Conditions (%) Tosylate (99.8%) 40° C./75% RH 98.580° C. 99.4 Ambient temperature and light 99.6 Fumarate (99.9%) 40°C./75% RH 97.5 80° C. 83.0 Ambient temperature and light 99.6

Example 17. Salt Disproportionation Studies

The scaled-up tosylate and fumarate salts were subjected to saltdisproportionation studies at ambient temperature. The followingobservations and results were obtained during these disproportionationstudies:

-   -   After stirring the tosylate salt at 20° C. in deionized water        for 30 min, pH =2.58. After 20 h at 20° C., pH was re-measured        and was found to be 2.53.    -   XRPD analysis of the post-slurry tosylate material indicated        that there was no change to the input Pattern 1 material.    -   After stirring the fumarate salt at 20° C. in deionized water        for 30 min, pH =3.50. After 20 h at 20° C., pH was re-measured        and was found to be 3.48.    -   XRPD analysis of the post-slurry fumarate material indicated        that the input Pattern 4 material had changed to a new pattern        (designated Pattern 5), suggesting further hydrate formation.

Example 18. Hydration Studies

Hydration studies in IPA at 3 different water activities (aw=0.368,0.608 and 0.911) were carried out using the scaled-up tosylate andfumarate salts at ambient temperature. The following observations andresults were obtained during these hydration studies:

-   -   After stirring the tosylate salt at 20° C. for 25 h in each of        the IPA/water mixtures prepared, XRPD analysis of the isolated        solids indicated that input Pattern 1 was unchanged after        hydration studies.    -   After stirring the fumarate salt at 20° C. for 24 h in each of        the IPA/water mixtures prepared, XRPD analysis of the isolated        solids indicated that input Pattern 4 had changed after the        hydration studies. Pattern 3 was obtained at lower aw values        (aw=0.368 and 0.608), while Pattern 5 was obtained at aw=0.911,        suggesting further hydration occurred. The analysis was carried        out on damp solids and it is likely that Pattern 3 would convert        back to Pattern 4 after drying.

Example 19. Thermodynamic Solubility Studies

Thermodynamic solubility studies in buffers at 3 different pH values (pH=1.2, 4.5 and 6.8) were carried out using the scaled-up tosylate andfumarate salts at ambient temperature. The following observations andresults were obtained during these thermodynamic solubility studies:

-   -   After creating slurries of the tosylate salt and stirring at        20° C. for ca. 15 min, pH values were checked and found to be        1.21, 4.23 and 6.55, respectively.    -   Adjusted tosylate slurries to pH 4.51 and 6.81, adding more        tosylate salt to pH =4.5 reaction to saturate.    -   After stirring the tosylate salt at 20° C. for 22 h in each        buffer solution, pH values checked again and found to be 1.22,        4.41 and 6.56, so adjusted final slurry to pH 6.76.    -   After stirring the tosylate salt at 20° C. for 24 h in each        buffer solution, XRPD analysis of the isolated solids indicated        that input Pattern 1 was unchanged after thermodynamic        solubility studies. HPLC analysis of the solutions indicated        that the solubility of the tosylate salt was relatively        unchanged by pH, with each pH giving a concentration of ca. 25        mg/mL (see Table 10 for details).    -   After creating slurries of the fumarate salt and stirring at        20° C. for ca. 15 min, pH values were checked and found to be        3.36, 3.63 and 3.73, respectively.    -   Adjusted fumarate slurries to pH 1.26, 4.51 and 6.88, adding        more fumarate salt to pH =4.5 and 6.8 reactions to saturate.    -   pH values for reactions which had more solid added were checked        again and found to be 3.36 and 4.50, so pH was adjusted to 4.41        and 6.76. All material dissolved in pH 6.8 buffer solution,        could not be saturated.    -   After stirring the fumarate salt at 20° C. for 22 h in each        buffer solution, pH values checked again and found to be 1.48,        4.45 and 6.56, so adjusted first slurry to pH 1.17.    -   After stirring the fumarate salt at 20° C. for 24 h in each        buffer solution, XRPD analysis of the isolated solids indicated        that input Pattern 4 was changed by the thermodynamic solubility        studies. pH 1.2 buffer solution resulted in isolation of fumaric        acid only, while pH 4.5 buffer solution resulted in isolation of        Pattern 5. No solid was isolated from pH 6.8 reaction.    -   HPLC analysis of the solutions indicated that the solubility of        the fumarate salt increases as the pH increases, with        solubility >173 mg/mL at pH 6.8.

TABLE F Thermodynamic Solubility Data for Tosylate and Fumarate SaltsBuffer Concentration by HPLC Salt Solution (pH) (mg/mL) Solid FormTosylate 1.2 23.8 Pattern 1 4.5 25.8 Pattern 1 6.8 24.3 Pattern 1Fumarate 1.2 35.1 Fumaric acid 4.5 123.1 Pattern 5

Example 20. Cholesteryl Sulfate Pattern 1 (Methanol)—XRPD Peak List

TABLE 1 Pos. [°2θ] Height [cts] Rel. Int. 4.9500 513.95 92.32 5.7914307.76 55.28 8.5140 76.04 13.66 9.8145 76.19 13.68 10.5199 86.72 15.5811.9028 157.46 28.28 12.3400 147.07 26.42 12.6450 148.79 26.73 13.1574136.33 24.49 16.0665 556.71 100.00 16.7594 510.78 91.75 17.0428 268.8048.28 19.0804 122.95 22.08 20.3368 52.81 9.49 20.7068 54.47 9.78 21.739756.11 10.08

Example 21. Cholesteryl Sulfate Pattern 2 (Acetonitrile:Ethylene glycol(90:10v/v))—XRPD Peak List

TABLE 2 Pos. [°2θ] Height [cts] Rel. Int. 7.4205 379.10 50.08 9.8832111.44 14.72 12.4010 227.72 30.08 13.0698 476.92 63.00 13.3833 205.7727.18 14.4079 157.67 20.83 15.0973 135.35 17.88 15.5537 408.19 53.9216.2771 756.98 100.00 16.8114 138.31 18.27 17.1732 106.30 14.04 17.4697127.72 16.87 17.7008 344.28 45.48 19.4681 157.41 20.79 19.8491 436.4657.66 22.8297 52.91 6.99 29.9651 45.41 6.00 32.5913 40.20 5.31

Example 22. Tosylate Pattern 1 (Acetonitrile:ethyleneglycol (90:10v/v))XRPD peak list

TABLE 3 Pos. [°2θ] Height [cts] Rel. Int. 6.3236 859.74 30.00 7.1904530.19 18.50 9.0662 300.72 10.49 11.1993 316.77 11.05 11.6515 1518.3652.99 11.8245 302.27 10.55 12.2481 1314.64 45.88 12.7291 509.38 17.7812.9196 384.25 13.41 13.4259 1529.40 53.37 13.9356 307.63 10.74 14.0866204.08 7.12 14.3102 270.76 9.45 14.7230 964.06 33.64 15.3518 1622.9556.64 15.7767 500.48 17.47 16.0824 764.78 26.69 16.6610 687.30 23.9916.9655 1363.75 47.59 17.4222 287.09 10.02 18.1176 865.70 30.21 18.9399814.95 28.44 19.5396 283.99 9.91 19.7829 437.17 15.26 20.0556 296.9910.36 20.2220 1287.25 44.92 21.6820 331.11 11.55 22.4522 2865.51 100.0022.7058 1681.25 58.67 23.1326 1392.27 48.59 23.3451 475.86 16.61 23.7455393.03 13.72 24.2204 316.19 11.03 24.5976 227.62 7.94 24.7839 256.188.94 25.6635 465.16 16.23 25.9383 704.34 24.58 27.0486 161.20 5.6327.7138 218.23 7.62 28.2876 111.69 3.90 28.5866 260.93 9.11 28.8350162.33 5.67 29.4111 188.53 6.58 29.7366 126.04 4.40 30.9351 44.63 1.5631.2970 64.72 2.26 31.8586 56.60 1.98 34.1666 162.54 5.67 34.7854 69.072.41

Example 23. Tosylate Pattern 2 (2 propanol): XRPD peak list

TABLE 4 Pos. [°2θ] Height [cts] Rel. Int. 6.5048 2925.31 67.47 7.0412810.71 18.70 9.0165 650.57 15.01 11.5522 1124.90 25.95 11.8465 1593.9636.76 12.0031 2406.52 55.51 12.4973 199.54 4.60 13.0115 2587.33 59.6813.2622 2635.53 60.79 14.2951 1029.41 23.74 14.4394 956.83 22.07 14.6700675.49 15.58 15.0149 1928.22 44.47 15.7182 3392.71 78.25 15.8732 1501.5734.63 16.0677 933.19 21.52 17.3224 3615.64 83.40 17.6596 808.05 18.6418.0742 225.60 5.20 19.3625 2665.67 61.48 19.5565 1674.71 38.63 19.69541034.21 23.85 20.0052 813.69 18.77 20.5458 2193.23 50.59 21.1722 788.7518.19 21.9749 706.83 16.30 22.4132 2019.52 46.58 22.7633 1338.07 30.8623.1157 4335.55 100.00 23.4474 490.16 11.31 23.7123 1792.36 41.3424.2578 1012.24 23.35 24.5249 179.58 4.14 25.0281 521.70 12.03 25.2220518.22 11.95 25.4124 735.02 16.95 26.1017 617.07 14.23 26.4002 530.8412.24 26.6640 415.81 9.59 27.2584 204.55 4.72 27.6862 544.26 12.5528.2087 368.13 8.49 28.4358 551.21 12.71 28.6690 403.71 9.31 29.0632210.51 4.86 29.7900 405.63 9.36 30.1856 453.96 10.47 31.7342 69.62 1.6132.5306 175.56 4.05 34.2641 117.22 2.70

Example 24. Mesylate Pattern 1 (Dichloromethane): XRPD peak list

TABLE 5 Pos. [°2θ] Height [cts] Rel. Int. 5.6855 550.41 14.15 6.02062660.22 68.38 10.3924 3890.21 100.00 10.9552 1726.69 44.39 11.1560953.53 24.51 11.6500 900.93 23.16 12.0524 1678.78 43.15 13.5772 776.5019.96 13.8529 388.77 9.99 14.7106 678.23 17.43 14.9409 2928.38 75.2815.2690 644.99 16.58 15.7091 1223.57 31.45 15.9920 1083.26 27.85 17.0746155.12 3.99 17.5076 883.72 22.72 17.9935 688.61 17.70 18.2959 949.3024.40 18.5258 438.92 11.28 18.7728 1576.09 40.51 19.6638 1736.88 44.6520.4019 3047.78 78.34 20.8566 1106.70 28.45 21.2027 1108.07 28.4821.3736 3408.70 87.62 21.6173 1442.13 37.07 22.0030 1007.70 25.9022.1468 952.47 24.48 22.4678 1464.52 37.65 22.9236 1346.02 34.60 23.4098190.08 4.89 24.1636 795.75 20.46 24.6355 626.92 16.12 24.8676 300.927.74 25.2453 286.57 7.37 25.4632 287.25 7.38 25.9375 1191.81 30.6426.4465 1452.00 37.32 27.2385 416.92 10.72 27.8576 510.92 13.13 28.1594703.92 18.09 28.6842 202.85 5.21 29.1886 351.92 9.05 30.2331 173.49 4.4630.8093 221.03 5.68 32.2440 218.36 5.61 32.6305 193.59 4.98 33.2034126.92 3.26 33.6754 134.92 3.47 34.5344 31.92 0.82

Example 25. Mesylate Pattern 2 (Acetone:water(90:10v/v)) : XRPD peaklist

TABLE 6 Pos. [°2θ] Height [cts] Rel. Int. 3.2104 975.97 68.56 4.3126813.06 57.12 5.9916 946.70 66.51 7.4447 164.30 11.54 9.3645 243.64 17.129.6885 336.45 23.64 9.9966 111.19 7.81 10.3209 187.08 13.14 11.8020216.19 15.19 12.0313 464.41 32.63 12.3878 434.07 30.49 12.7870 736.0551.71 13.6046 239.65 16.84 14.3857 279.19 19.61 14.5904 598.83 42.0714.9160 239.19 16.80 15.1627 226.19 15.89 15.7759 561.39 39.44 15.9359474.05 33.30 16.3636 263.96 18.54 17.5056 812.69 57.09 18.0062 222.1915.61 18.4116 596.47 41.90 18.9363 1037.27 72.87 19.4525 669.71 47.0519.7728 447.25 31.42 20.1145 373.21 26.22 20.6143 1423.42 100.00 21.3512684.84 48.11 22.1408 299.87 21.07 22.7308 820.20 57.62 23.2392 635.6044.65 23.8175 633.78 44.52 24.0397 550.19 38.65 24.8469 492.27 34.5825.4521 384.31 27.00 26.0833 384.19 26.99 26.6795 195.49 13.73 27.1575113.19 7.95 27.8454 145.62 10.23 28.7187 183.33 12.88 29.7607 99.03 6.9631.1650 92.04 6.47 32.1555 64.60 4.54 33.2176 88.18 6.19

Example 26. Oxalate Pattern 1 (2-propanol) : XRPD peak list

TABLE 7 Pos. [°2θ] Height [cts] Rel. Int. 4.9532 1449.82 100.00 6.1637198.63 13.70 7.2943 1236.55 85.29 7.7207 90.75 6.26 8.3148 116.52 8.049.8933 275.73 19.02 10.0378 341.64 23.56 12.2572 389.69 26.88 13.1795436.58 30.11 13.3769 989.08 68.22 13.9612 300.49 20.73 14.5695 143.199.88 14.8668 290.57 20.04 15.0420 384.10 26.49 16.1696 466.54 32.1816.4614 357.10 24.63 17.2938 581.79 40.13 18.0668 527.73 36.40 18.6224398.01 27.45 19.4090 282.71 19.50 19.6513 143.92 9.93 20.1142 481.1233.18 20.4050 236.98 16.35 20.6432 109.39 7.55 21.3207 655.65 45.2222.0879 222.23 15.33 22.5352 735.64 50.74 22.8692 1366.32 94.24 23.3140516.04 35.59 24.0468 258.86 17.85 24.3692 542.51 37.42 24.7043 756.1052.15 25.7054 166.45 11.48 26.1300 189.65 13.08 26.6847 340.50 23.4927.4517 354.35 24.44 28.5093 90.89 6.27 29.3658 143.23 9.88 29.8396139.91 9.65 30.2682 96.42 6.65 31.3451 94.72 6.53 31.6554 117.78 8.1233.2878 48.96 3.38 34.2219 129.90 8.96

Example 27. Oxalate Pattern 2 (Acetone:water(90:10v/v)) : XRPD peak list

TABLE 8 Pos. [°2θ] Height [cts] Rel. Int. 3.8204 1023.49 74.65 4.26941006.07 73.38 5.6244 367.95 26.84 6.5112 296.13 21.60 6.9639 495.4636.14 8.1270 1093.19 79.74 9.0666 199.42 14.55 10.3663 393.99 28.7410.7413 205.63 15.00 11.3178 123.75 9.03 11.7667 96.25 7.02 12.3780297.43 21.69 13.0244 156.89 11.44 13.6355 398.52 29.07 14.4623 337.5924.62 14.8263 177.63 12.96 15.3745 252.52 18.42 15.7939 185.74 13.5516.4008 358.23 26.13 16.9166 290.61 21.20 17.3729 249.95 18.23 17.6682438.94 32.02 18.1633 935.58 68.24 18.3587 513.22 37.43 19.0634 774.2356.47 19.8595 594.91 43.39 20.3863 720.10 52.52 20.7089 1370.99 100.0021.1449 567.18 41.37 22.3294 980.33 71.51 22.7660 691.29 50.42 23.1962575.17 41.95 23.5383 572.83 41.78 23.9992 539.12 39.32 24.5505 555.7540.54 24.9379 667.00 48.65 25.6244 614.75 44.84 26.9282 433.69 31.6328.5609 105.52 7.70 29.4356 100.05 7.30

Example 28. Esylate Pattern 1 (2-Propanol) : XRPD peak list

TABLE 9 Pos. [°2θ] Height [cts] Rel. Int. 5.4182 2523.05 94.32 5.7226212.08 7.93 9.4519 452.55 16.92 9.7709 1461.39 54.63 10.8340 1561.3858.37 11.0000 596.90 22.31 11.7890 856.82 32.03 13.3227 284.21 10.6213.5503 332.12 12.42 13.9236 430.32 16.09 14.3536 747.32 27.94 14.6610494.56 18.49 14.7960 345.01 12.90 15.0602 766.95 28.67 15.5639 1009.5437.74 15.7577 340.61 12.73 16.2767 220.92 8.26 17.1600 869.09 32.4917.4509 539.09 20.15 17.6937 828.03 30.95 18.1813 551.23 20.61 18.81801248.82 46.68 18.9824 921.79 34.46 19.6693 1256.96 46.99 20.5851 440.6616.47 21.0850 2675.13 100.00 21.4834 1003.94 37.53 21.7565 1053.26 39.3722.0457 598.68 22.38 22.3107 1111.79 41.56 23.1703 390.24 14.59 23.7448761.15 28.45 23.9081 518.70 19.39 24.4576 669.04 25.01 24.9599 180.896.76 25.5780 445.56 16.66 25.9086 549.74 20.55 26.6417 432.04 16.1527.2891 219.88 8.22 27.5817 513.64 19.20 28.5785 121.48 4.54 28.9965198.67 7.43 29.5971 63.81 2.39 30.1716 75.23 2.81 30.3897 125.06 4.6731.0846 78.32 2.93

Example 29. Esylate Pattern 2 (Anisole) : XRPD peak list

TABLE 10 Pos. [°2θ] Height [cts] Rel. Int. 5.4123 986.96 48.69 9.6642668.83 32.99 9.9532 408.46 20.15 10.7777 726.81 35.85 10.9908 799.0639.42 11.8302 446.75 22.04 13.3865 252.22 12.44 13.9832 249.01 12.2814.5130 731.84 36.10 15.0235 640.93 31.62 15.6073 474.86 23.43 15.9886701.76 34.62 17.2884 778.18 38.39 17.7412 619.42 30.56 18.7012 824.1940.66 19.5647 937.99 46.27 20.0217 500.05 24.67 21.0255 2027.09 100.0021.3918 819.86 40.45 22.0785 718.65 35.45 22.8159 382.14 18.85 23.6802462.10 22.80 24.0516 632.10 31.18 25.8493 371.20 18.31 26.9534 273.6913.50 27.7402 172.31 8.50 28.1612 167.16 8.25 29.2755 127.69 6.3030.5014 61.30 3.02

Example 30. Fumarate Pattern 1 (2 propanol) : XRPD peak list

TABLE 11 Pos. [°2θ] Height [cts] Rel. Int. 3.6528 2721.00 100.00 5.3346401.76 14.77 6.1921 208.30 7.66 7.1693 749.52 27.55 7.2584 398.16 14.637.9555 181.24 6.66 8.2989 210.29 7.73 9.2514 50.60 1.86 10.5913 111.174.09 11.1450 749.78 27.56 12.0332 984.10 36.17 12.7127 293.05 10.7713.1965 569.63 20.93 13.5693 214.22 7.87 13.8163 306.41 11.26 14.3773502.19 18.46 14.6066 328.44 12.07 15.3422 429.47 15.78 15.5476 423.3515.56 15.9810 889.19 32.68 16.6013 379.65 13.95 17.5327 244.32 8.9817.8949 857.50 31.51 18.2706 629.17 23.12 19.0516 721.07 26.50 19.3988568.32 20.89 19.8836 128.89 4.74 20.2075 281.33 10.34 20.3963 232.838.56 20.7842 396.46 14.57 21.1854 981.38 36.07 21.8139 347.14 12.7622.0119 356.63 13.11 22.4021 210.78 7.75 22.6620 465.25 17.10 22.99951733.03 63.69 23.2815 829.33 30.48 23.5370 509.46 18.72 23.9934 492.0518.08 24.6748 1605.41 59.00 24.8788 1430.78 52.58 25.7236 1394.90 51.2626.0766 544.72 20.02 26.8205 498.71 18.33 27.8212 471.32 17.32 28.5683563.10 20.69 28.9477 276.52 10.16 29.3638 462.18 16.99 30.7259 388.3314.27 32.1373 247.81 9.11

Example 31. Fumarate Pattern 2 (Acetone:water(90:10v/v)) : XRPD peaklist

TABLE 12 Pos. [°2θ] Height [cts] Rel. Int. 4.2283 814.45 93.20 5.2902418.95 47.94 5.7064 189.90 21.73 7.0087 103.69 11.87 7.2740 88.69 10.158.4471 125.02 14.31 10.2953 253.66 29.03 10.4698 121.69 13.93 11.1043142.69 16.33 11.2764 457.42 52.34 11.6690 474.89 54.34 12.0243 312.6935.78 12.3661 439.60 50.30 12.6972 410.41 46.96 13.0211 360.84 41.2913.2807 409.51 46.86 14.8277 449.89 51.48 15.4615 354.89 40.61 15.8235312.69 35.78 16.0773 278.69 31.89 16.9930 478.20 54.72 17.2436 561.5364.26 18.1053 374.04 42.80 19.5434 216.62 24.79 20.7010 868.87 99.4321.1934 354.94 40.62 21.9721 221.69 25.37 22.2605 256.69 29.37 22.6296476.69 54.55 23.6035 873.89 100.00 23.7351 738.81 84.54 24.0613 490.7156.15 24.4738 567.73 64.97 24.9772 542.00 62.02 25.5868 252.89 28.9426.0270 293.74 33.61 27.2637 172.10 19.69 27.9596 217.37 24.87 28.5769248.86 28.48 30.7356 73.69 8.43 31.2491 124.49 14.25

Example 32. Fumarate Pattern 3 (2-propanol/water (re-preparations)) :XRPD peak list

TABLE 13 Pos. Height Rel. 4.6078 1598.29 100.00 4.7247 702.13 43.935.6369 90.25 5.65 5.7945 429.87 26.90 6.9083 392.40 24.55 7.2036 260.4216.29 7.4378 61.20 3.83 9.2520 317.93 19.89 9.3801 258.93 16.20 10.0352411.00 25.72 10.3048 49.93 3.12 11.1685 1150.19 71.96 11.4467 511.9332.03 11.7464 234.39 14.66 12.7059 133.93 8.38 13.1603 736.16 46.0613.3277 641.44 40.13 13.6611 593.75 37.15 14.2278 408.21 25.54 14.63221171.55 73.30 14.9188 384.93 24.08 15.0644 561.47 35.13 15.7469 676.5242.33 15.9535 507.66 31.76 16.2032 678.88 42.48 16.3240 547.82 34.2816.6769 329.75 20.63 17.4243 429.52 26.87 18.2889 699.16 43.74 18.8043697.95 43.67 19.2960 874.40 54.71 19.5746 1017.59 63.67 19.9329 1062.6066.48 20.2723 876.82 54.86 20.5228 1501.47 93.94 21.1443 770.54 48.2121.5244 426.96 26.71 21.7014 707.54 44.27 22.0764 276.93 17.33 22.3112634.93 39.73 22.3752 708.93 44.36 22.6648 541.01 33.85 22.8586 880.2455.07 23.1084 959.94 60.06 23.2825 1037.93 64.94 23.5664 839.66 52.5323.9441 420.93 26.34 24.1708 1003.05 62.76 24.2438 1135.70 71.06 24.5667960.38 60.09 24.7979 626.93 39.22 25.2094 1204.78 75.38 25.5564 859.7653.79 26.3596 605.93 37.91 26.4901 804.07 50.31 26.8577 710.95 44.4827.3567 818.89 51.24 27.6722 410.93 25.71 28.0031 379.93 23.77 28.3434638.30 39.94 28.6121 378.12 23.66 29.0080 437.12 27.35 29.5671 326.9920.46 30.6297 327.67 20.50 31.2974 414.54 25.94 31.9650 372.80 23.3232.3013 217.89 13.63 33.4812 144.06 9.01 33.9277 154.89 9.69 34.2253139.09 8.70

Example 33. Fumarate Pattern 4 (2-propanol/water (scale-up)) : XRPD peaklist

TABLE 14 Pos. [°2θ] Height [cts] Rel. Int. 4.8468 300.55 46.00 7.2009154.02 23.57 9.2287 237.04 36.28 9.8752 104.03 15.92 11.3790 573.8087.82 12.3753 158.81 24.31 13.1003 208.76 31.95 13.3414 399.37 61.1314.0505 653.36 100.00 14.4103 194.23 29.73 14.9682 205.60 31.47 15.5626147.16 22.52 16.0210 407.61 62.39 16.2253 421.58 64.52 16.5208 189.4328.99 16.8847 140.67 21.53 17.3260 190.98 29.23 18.0436 155.62 23.8218.5063 215.33 32.96 19.5667 509.39 77.97 19.8049 496.12 75.93 20.4746198.51 30.38 21.3412 286.69 43.88 21.6458 400.04 61.23 21.8878 323.7349.55 22.4062 336.53 51.51 22.9397 499.51 76.45 23.2065 497.08 76.0823.6258 468.15 71.65 23.8043 304.27 46.57 24.2839 509.97 78.05 24.5292587.59 89.93 24.9422 271.15 41.50 25.6526 466.21 71.36 26.2095 247.4737.88 26.5712 391.53 59.93 26.8039 269.49 41.25 27.3245 242.24 37.0827.9402 292.13 44.71 28.3452 197.75 30.27 29.7807 187.95 28.77 30.4185177.79 27.21 32.4348 153.96 23.56 33.9687 84.19 12.88

Example 34. Fumarate Pattern 5 (Pattern 4 after slurrying in water) :XRPD peak list

TABLE 15 Pos. [°2θ] Height [cts] Rel. Int. 5.2173 220.55 20.66 6.5788368.80 34.54 10.4657 144.23 13.51 11.9526 279.79 26.21 12.2981 647.1260.61 12.9633 131.78 12.34 13.1469 479.18 44.88 13.6532 355.99 33.3513.9226 103.85 9.73 14.0801 106.90 10.01 14.8387 127.52 11.94 15.2947229.73 21.52 15.7415 182.38 17.08 16.0705 365.39 34.23 17.0800 148.8313.94 17.8037 173.34 16.24 18.0998 187.12 17.53 19.2649 130.59 12.2319.6536 485.96 45.52 20.4686 317.43 29.73 20.9891 623.39 58.39 21.5138280.59 26.28 22.3786 233.51 21.87 23.1604 615.28 57.63 24.0181 580.9754.42 24.7153 601.56 56.35 25.0063 550.78 51.59 25.3823 980.84 91.8726.0374 1067.59 100.00 26.3551 541.45 50.72 27.5053 631.24 59.13 28.0100468.63 43.90 28.7269 530.89 49.73 31.3366 242.78 22.74 32.4594 166.7615.62

Example 35. Fumarate Pattern 6 (Acetonitrile during re-preparations) :XRPD peak list

TABLE 16 Pos. [°2θ] Height [cts] Rel. Int. 6.6183 167.28 12.44 7.3884246.01 18.30 7.6111 259.01 19.26 8.2981 533.31 39.66 8.8993 303.39 22.5610.0751 355.47 26.44 11.1019 442.91 32.94 11.5582 131.47 9.78 11.8344584.24 43.45 12.2224 200.75 14.93 12.9751 524.10 38.98 13.4040 681.1150.65 13.8874 390.10 29.01 14.2668 353.00 26.25 14.4971 388.85 28.9215.0582 391.06 29.08 15.7548 421.12 31.32 16.3188 693.31 51.56 17.3388354.15 26.34 17.9628 380.24 28.28 18.5415 806.29 59.96 18.9064 452.1333.63 19.4667 197.47 14.69 19.7556 249.47 18.55 20.1836 381.08 28.3420.7747 485.66 36.12 21.5446 910.06 67.68 22.2369 954.05 70.95 22.6652512.47 38.11 23.0991 996.00 74.07 23.6074 772.71 57.47 23.8948 969.0372.07 24.1368 1344.60 100.00 24.5986 1088.47 80.95 25.2568 845.47 62.8825.9952 1088.47 80.95 26.9499 765.80 56.95 27.4845 598.47 44.51 27.8343616.98 45.89 28.8828 718.59 53.44 29.2983 529.41 39.37 29.6677 397.4729.56 30.1333 438.47 32.61 30.7281 355.12 26.41 31.5937 297.97 22.1632.9662 297.45 22.12 33.8294 357.74 26.61

Example 36. Fumarate Pattern 7 (1-butanol during re-preparations) : XRPDpeak list

TABLE 17 Pos. [°2θ] Height [cts] Rel. Int. 5.2074 268.12 33.24 6.5759404.19 50.11 10.4268 127.44 15.80 11.9087 131.25 16.27 12.2972 298.8137.05 12.8749 71.33 8.84 13.0948 244.23 30.28 13.6525 304.82 37.7915.2610 169.55 21.02 15.7084 213.10 26.42 16.0248 319.57 39.62 16.4827138.83 17.21 17.0200 192.29 23.84 17.7452 374.39 46.42 18.0663 356.5044.20 19.2467 306.47 38.00 19.6260 691.53 85.74 20.4182 523.72 64.9320.9504 806.57 100.00 21.1080 425.98 52.81 21.4534 378.56 46.94 22.2977291.42 36.13 23.1512 675.69 83.77 23.9912 498.57 61.81 24.6413 358.9144.50 24.9511 330.70 41.00 25.3280 703.69 87.24 25.9830 803.85 99.6626.2805 402.66 49.92 27.4563 341.45 42.33 28.6746 215.20 26.68 29.657379.39 9.84 31.2290 55.54 6.89 32.3846 115.96 14.38

Example 37. Fumarate Pattern 8 (1-propanol during re-preparations) :XRPD peak list

TABLE 18 Pos. [°2θ] Height [cts] Rel. Int. 4.7133 245.00 17.67 7.0625304.40 21.95 7.8327 461.97 33.31 9.4373 496.45 35.80 10.8320 66.07 4.7611.2560 445.24 32.10 11.5530 251.70 18.15 12.1400 140.07 10.10 12.4180370.12 26.69 13.2125 717.58 51.74 13.6676 285.64 20.60 14.1438 152.0710.97 14.5314 276.64 19.95 14.8391 408.01 29.42 15.5031 163.07 11.7615.6570 224.07 16.16 15.9242 298.95 21.56 16.2469 212.07 15.29 16.7975366.37 26.42 18.0638 471.80 34.02 18.2986 344.07 24.81 18.6074 480.3234.63 18.9236 393.71 28.39 19.0681 270.07 19.47 19.8194 287.71 20.7520.2669 556.94 40.16 21.3752 584.86 42.17 21.6758 434.07 31.30 21.9446671.16 48.39 22.6951 747.22 53.88 23.2295 486.07 35.05 23.6142 575.0741.47 24.0109 597.00 43.05 24.4314 1382.12 99.66 25.2281 315.07 22.7225.5842 1386.85 100.00 26.1514 271.07 19.55 26.7925 471.07 33.97 27.1916319.07 23.01 28.1339 392.84 28.33 28.5109 507.45 36.59 29.2877 309.0022.28 29.7222 174.07 12.55 30.6360 158.05 11.40 31.3505 190.37 13.7332.6032 78.07 5.63 32.9347 116.91 8.43 33.8939 121.17 8.74

Example 38. Benzoate Pattern 1 (2-propanol) : XRPD peak list

TABLE 19 Pos. [°2θ] Height [cts] Rel. Int. 5.0941 297.32 88.69 10.2223204.91 61.12 11.8691 118.15 35.24 13.2023 335.24 100.00 13.7755 152.5045.49 13.9773 333.43 99.46 14.6467 79.62 23.75 15.9075 105.86 31.5816.7186 110.67 33.01 20.4020 333.47 99.47 21.9198 189.30 56.47 23.0969155.88 46.50 23.5325 274.39 81.85 24.4800 164.22 48.99 25.2794 134.0039.97

Example 39. Succinate Pattern 1 (Acetone: Water (90:10v/v)) : XRPD peaklist

TABLE 20 Pos. [°2θ] Height [cts] Rel. Int. 4.1731 1536.07 100.00 5.1086286.72 18.67 6.5676 392.68 25.56 7.9847 195.87 12.75 9.9321 359.08 23.3810.3453 201.93 13.15 11.9442 155.73 10.14 13.1111 175.20 11.41 14.0979247.70 16.13 14.5776 178.59 11.63 14.8894 146.58 9.54 15.4458 148.779.69 16.0064 120.74 7.86 17.5761 211.01 13.74 18.0178 481.64 31.3618.5153 181.50 11.82 18.9551 172.30 11.22 19.2662 76.74 5.00 19.9186168.28 10.96 20.3646 146.23 9.52 20.8102 173.87 11.32 21.1557 110.747.21 22.1676 196.95 12.82 22.3940 214.45 13.96 22.8184 164.74 10.7223.2383 98.74 6.43 23.3762 186.57 12.15 24.1177 306.10 19.93 25.1899125.90 8.20 25.5494 116.29 7.57 26.0776 68.02 4.43 27.5686 85.74 5.58

Example 40. Preparation of Tosylate Pattern 2

MTP-131 tosylate (35 mg) was dissolved in the minimum quantity ofmethanol in a 20 mL clear glass vial and tBME (approx. 300 μL) addeduntil slight turbidity was noticed. This vial was capped and temperaturecycled between 5 and 30 ° C. After one week, lath-like crystals werenoted to have grown below the solution meniscus, that appeared suitablefor interrogation by single crystal X-ray diffraction.

Example 41. Single Crystal X-ray Analysis (SXRD) of Tosylate Pattern 2

A colourless fragment of a lath (0.46×0.07×0.03 mm) was used in thesingle crystal diffraction study. The crystal was coated with Paratoneoil and data collected on a Rigaku Oxford Diffraction (Dual Source)SuperNova diffractometer using mirror monochromated Cu Kα (λ=1.54184 Å,40 kV/40 mA) radiation at 120(1) K using an Oxford Cryosystems 700+ lowtemperature device and Atlas CCD plate detector (Rigaku OxfordDiffraction). A total of 2672 frames were collected for a hemisphere ofreflections using a ω strategy calculated by CrysAlisPro (Rigaku OxfordDiffraction 1.171.38.43h, 2015) over the θ range 3.14-77.17° with 1°step size and 2 sec/frame exposure. Frames were integrated usingCrysAlisPro (Rigaku Oxford Diffraction 1.171.38.43h, 2015) to amonoclinic cell using a moving average background, yielding a total of52633 reflections, of which 17979 were independent (I>2σ(I)). Data wereintegrated to 2θmax=154.34° (95.3% completeness), and fixed to2θfull=98.1° (98.1% completeness). Absorption corrections were appliedusing SADABS (Bruker 2001. Bruker AXS Inc., Madison, Wis., USA) using amulti-scan model (absorption coefficient=1.732 mm-1).

The OLEX2 graphical software package was used as an interface for phasedetermination and structure refinement. Data were solved using directmethods (SHELXS97) and developed by full least squares refinement on F2(SHELXL97) in the monoclinic space-group P21 (E2−1=0.731). A search forhigher metric symmetry using the ADDSYMM routine of PLATON wasattempted, but failed to uncover any higher order symmetry. Allnon-hydrogen atoms were located in the Fourier map and their positionsrefined prior to describing their thermal movement of all non-hydrogenatoms anisotropically. Within the asymmetric unit, one complete,crystallographically independent MTP-131 formula unit, three associatedp-tolyl-counterions, one fully occupied water molecule and one fullyoccupied methanol molecule were found. No disorder was modelled in thefinal structure. All hydrogen atoms were placed in calculated positionsusing a riding model with fixed Uiso at 1.2 times for all CH and CH₂groups, and 1.5 times for all CH₃ and OH groups. The Flack parameter wasrefined to 0.017(10) for 4760 select quotients. Note: The Flackparameter is used to determine chirality of the crystal studied, thevalue should be near 0, a value of 1 means that the stereochemistry iswrong and the model should be inverted. A value of 0.5 means that thecrystal consists of a racemic mixture of the two enantiomers. Thehighest residual Fourier peak was found to be 0.39 e.Å⁻³ approx. 0.87 Åfrom O(9), and the deepest Fourier hole was found to be −0.45 e.Å⁻³approx. 0.71 Å from S(3).

Crystal Data

C₅₄H₇₉N₉O₁₆S₃ (M=1206.44 g/mol): monoclinic, space group P21 (no. 4),a=7.98250(10) Å, b=26.9673(4) Å, c=14.5556(3) Å, β=104.770(2)°,V=3029.80(9) Å3, Z=2, T=120.01(10) K, μ(CuKα)=1.732 mm-1, Dcalc=1.322g/cm3 , 52633 reflections measured (6.28°≤2θ≤154.348°), 12237 unique(Rint=0.0753, Rsigma=0.0723) which were used in all calculations. Thefinal R1 was 0.0512 (I>2σ(I)) and wR2 was 0.1325 (all data).

Example 42. Structural features of Tosylate Pattern 2

Sample features include:

-   -   The unit cell dimensions of the collected structure were found        to be as follows:

Monoclinic P21 a = 7.98250(10) Å α = 90° b = 26.9673(4) Å β =104.770(2)° c = 14.5556(3) Å γ = 90° Volume = 3029.80(9) Å3 Z = 2, Z′ =1

-   -   The asymmetric unit was found to contain one complete,        crystallographically independent MTP-131 formula unit, three        associated p-tolulenesulfonate counterions, one fully occupied        advantageous water molecule and one fully occupied methanol        molecule, as shown in Figure.    -   The final refinement parameters were as follows:

R1[I>2σ(I)]=5.12%

GooF (Goodness of fit)=1.029

wR2 (all data)=13.25%

Rint=7.53%

-   -   The model is suitable to confirm the connectivity and        stereochemistry of the parent MTP-131 molecule, as shown below:

-   -   Calculated from the above structure, and using FIG. 30 or FIG.        34 as references, the chiral centers present in the analyzed        MTP-131 tosylate, Pattern 2 crystal are summarized below. Note:        Numbering in this structure is not according to systematic IUPAC        guidelines.

-   C5—R

-   C7—S

-   C18—S

-   C24—S    -   Protonation of the arginine side-chain was confirmed by        inspection of the guanidinium bond lengths, where two were found        to be near identical, measuring C(1)-N(1) 1.338(6) Å/C(1)-N(3)        1.336(6) Å, while C(1)-N(2) was found to measure 1.322(6) Å.        Nitrogen atoms N(4) and N(7) were also found to be quaternary.    -   The structure of MTP-131 tosylate, Pattern 2 showed the        stoichiometric hydrated and solvated nature of the form wherein        one fully occupied water molecule and one fully occupied        methanol molecule per MTP-131 formula unit were found.    -   No notable π . . . . π interactions were observed in the        structure implying packing within the structure is predominately        stabilized by hydrogen-bonding between MTP-131,        tosylate-counterions and solvent molecules, alongside a number        of weak intermolecular forces (namely between short-atom        contacts).    -   The p-tolyl-counteranions were found to offer a complex hydrogen        bonding network between adjacent MTP-131 parent molecules. The        crystallized solvent molecules were also found to be integral        hydrogen bond donors and acceptors with moderate strength and        found within the same pocket, as shown in FIG. 35.        Key separations were found to be as following:

H(5A) . . . O(9) 1.963(4) Å O(9) . . . H(16)^(i) 2.138(6) Å O(16)^(i) .. . H(7B) 2.062(4) Å H(7A) . . . O(15) 1.836(3) Å H(15) . . . O(2)^(I)1.918(3) Å Symmetry code: (i) +x, +y, −1 + z.

-   -   When viewed along unit cell axes a, b and c, the structure was        found to be tightly packed as shown in FIG. 30 - FIG. 32 and        confirmed in the calculated density 1.322 g·cm⁻³    -   A simulated XRPD diffractogram has been calculated (FIG. 35) and        compared to experimental (room temperature) data (FIG. 36).        Excellent overlap has been observed between simulated        diffractogram and previously prepared MTP-131 tosylate, Pattern        2.

TABLE 21 Crystallographic parameters and refinement indicators ofMTP-131, Pattern 2. MTP-131, Form 2 Empirical formula C₅₄H₇₉N₃O₁₀S₃Formula weight 1206.44 Temperature/K 120(1) Crystal system monoclinicSpace group P2₁ a/Å 7.98250(10) b/Å 26.9673(4) c/Å 14.5556(3) α/° 90 β/°104.770(2) γ/° 90 Volume/Å³ 3029.80(9) Z, Z′ 2 ρ_(calc) g/cm³ 1.322μ/mm⁻¹ 1.732 F(000) 1284.0 Crystal size/mm³ 0.463 × 0.072 × 0.026Radiation CuKα (λ = 1.54178) 2Θ range for data collection/° 6.28 to154.348 Index ranges −7 ≤ h ≤ 10, −31 ≤ k ≤ 33, −18 ≤ l ≤ 18 Reflectionscollected 52633 Independent reflections 12237 [R_(int) = 0.0753,R_(sigma) = 0.0723] Data/restraints/parameters 12237/1/752 S 1.029 FinalR indexes [F² > 2σ (F²)] R₁ = 0.0512, wR₂ = 0.1300 Final R indexes [alldata] R₁ = 0.0552, wR₂ = 0.1325 Δρmax , Δρmin/e Å⁻³ 0.39/−0.44 FlackParameter 0.017(10) R₁ = (Σ|F_(o)| − |F_(c)|)/Σ|F_(o)|); wR₂ ={Σ[w(F_(o) ² − F_(c) ²)²]/Σ[w(F_(o) ²)²]

} S = (Σ[w(F_(o)2 − F_(c) ²)²]/(n − p))

indicates data missing or illegible when filed

TABLE 22 Fractional Atomic Coordinates (×104) and Equivalent IsotropicDisplacement Parameters (Å2 × 103) for MTP-131 tosylate, Pattern 2. Ueqis defined as ⅓ of the trace of the orthogonalised UIJ tensor. Atom x yz U(eq) C1 9503(5) 6963.4(17) 3816(3) 28.9(8) N1 10146(5)  7079.7(16)4732(3) 32.5(8) O1 5861(4) 4987.9(11) 2263(2) 27.2(6) C2 6822(5)6839.7(16) 2510(3) 29.4(8) N2 10557(5)  6828.9(15) 3292(3) 32.2(8) O21490(4) 4398.6(13) 6762(2) 31.9(6) C3 6619(5) 6281.6(15) 2338(3) 24.8(7)N3 7784(5) 6976.1(15) 3469(3) 30.9(7) O3 −168(3) 5093.1(12) 1954(2)29.8(6) S3 3799.0(11)  4395.8(3)  9238.4(7)  24.6(2) C4 5260(5)6186.8(14) 1413(3) 23.2(7) N4 6703(4) 5467.6(13)  854(2) 22.5(6) O4 141(4) 3549.1(11) 3848(2) 27.0(6) C5 5087(4) 5642.4(14) 1102(3) 21.0(7)N5 3228(4) 5358.2(12) 2070(2) 22.3(6) O5 −5744(3)  4048.4(11) 3720(2)28.1(6) C6 4764(5) 5291.5(14) 1873(3) 20.5(7) N6  886(4) 4395.0(12)2787(2) 20.6(6) C7 2779(4) 5102.6(14) 2860(3) 20.2(7) N7 −2201(4) 4333.4(16) −1288(3)  32.6(8) C8 2689(5) 5482.9(14) 3642(3) 22.9(7) N8−2519(4)  3897.3(13) 3628(2) 23.0(6) C9 2389(5) 5226.8(14) 4514(3)22.1(7) N9 −6023(4)  3256.3(13) 4168(3) 28.5(7) C10 3792(5) 5021.4(15)5187(3) 23.9(7) C11 3525(5) 4748.9(16) 5951(3) 26.2(8) C12 1855(5)4678.8(16) 6043(3) 25.4(8) O12 4092(4) 4220.7(12) 8334(2) 29.6(6) C13 454(5) 4900.0(16) 5405(3) 24.9(7) O13 5290(4) 4664.6(12) 9799(2)34.2(7) C14  713(5) 5182.0(15) 4650(3) 23.8(7) O14 2180(4) 4669.7(13)9101(3) 36.3(7) C15 5625(5) 5107.5(17) 5114(3) 27.9(8) C16 −834(5)5451.4(18) 4027(3) 31.5(9) O16 −430(5) 5146.7(14) 9754(3) 40.7(8) C171016(5) 4856.4(14) 2487(3) 21.2(7) C18 −797(4) 4135.8(14) 2564(3)20.3(7) C19 −1000(5)  3770.2(15) 1729(3) 24.6(7) C20 −941(5) 4024.7(15) 800(3) 24.8(7) C21 −1383(6)  3669.7(16)  −44(3) 29.1(8) C22 −1094(5) 3887.9(17) −951(3) 29.8(8) C23 −976(5) 3838.9(15) 3428(3) 22.6(7) C24−3108(5)  3596.7(15) 4322(3) 22.0(7) C25 −5095(5)  3647.4(15) 4042(3)21.5(7) C26 −2348(5)  3798.9(16) 5343(3) 27.3(8) C27 −2746(6) 3489.8(16) 6123(3) 31.7(9) C28 −1527(10)  3160(2) 6653(4)  52.8(15) C29−2004(15)  2876(2) 7392(4)  80(3) C30 −3581(16)  2929(3) 7574(5)  83(3)C31 −4723(12)  3246(3) 7061(5)  75(3) C32 −4336(8)   3526(2) 6341(4) 43.7(12) C47 3629(5) 3858.2(16) 9898(3) 25.6(8) C48 3889(6) 3895.8(17)10876(3)  30.6(8) C49 3674(6) 3477.5(19) 11391(3)   36(1) C50 3206(6)3020.3(18) 10950(4)   35.8(10) C51 2967(7) 2988.3(18) 9969(4)  38.7(10)C52 3179(6) 3406.8(17) 9437(3) 32.5(9) C53 2946(6)  2574(2) 11523(5)  52.3(15) S1 14930.6(12)  6993.9(3)  5046.6(7)  25.4(2) O6 13742(4) 7393.6(11) 5151(2) 28.8(6) O7 16715(4)  7174.5(12) 5203(2) 32.3(6) O814317(4)  6722.6(12) 4148(2) 32.8(6) C33 14888(5)  6578.1(14) 5970(3)25.9(8) C34 16126(6)  6614.0(17) 6840(3) 31.1(9) C35 15932(6) 6325.9(18) 7602(3)  35.8(10) C36 14542(6)  6000.2(18) 7501(3) 35.0(9)C37 13340(6)  5969.2(16) 6628(4) 33.5(9) C38 13491(5)  6253.2(16)5858(3) 29.4(8) C39 14376(9)   5693(2) 8341(4)  53.5(14) S2 −132.1(12) 6467.2(4)  562.3(8)  30.6(2) O9  985(5) 6038.4(19)  890(4)  71.7(17) O10 −54(8) 6850.6(19) 1273(3)  68.9(16) O11 −1891(4)  6304.2(13)  117(2)33.5(7) C40  664(5) 6738.5(14) −343(3) 24.7(8) C41 1520(6) 7192.3(17)−208(3) 29.9(8) C42 2088(6) 7403.2(18) −947(4) 33.5(9) C43 1786(6)7173.7(18) −1833(4)  33.2(9) C44  964(6)  6716(2) −1952(4)   39.6(11)C45  418(6) 6497.1(18) −1218(4)   35.8(10) C46 2282(7)  7421(2)−2658(4)   46.3(12) O15 −1385(4)  4777.5(13) −2797(2)  32.7(6) C54−1062(8)   5297(2) −2634(4)   45.1(11)

TABLE 23 Anisotropic Displacement Parameters (Å2 × 103) for MTP-131Tosylate, Pattern 2. The Anisotropic displacement factor exponent takesthe form: −2π2 [h2 a*2U11 + 2hka*b*U12+]. Atom U₁₁ U₂₂ U₃₃ U₂₃ U₁₃ U₁₂C1 27.4(19)  26(2)  34(2) 1.1(16) 9.3(16) −3.6(16) N1 24.8(16)  41(2)32.6(18) −4.5(15)  9.5(14) −4.1(14) O1 19.6(12) 27.7(15) 36.0(15)8.5(12) 10.1(11)   5.5(10) C2  28(2)  22(2)  37(2) −1.8(16)  6.1(16)−0.4(15) N2 26.4(17)  38(2) 34.0(18) −3.3(15)  10.4(14)  −6.0(14) O227.1(14) 38.3(17) 30.2(14) 9.9(13) 7.2(11) −2.5(12) C3 21.2(17) 21.1(19)32.7(19) 1.6(15) 8.0(15) −0.2(13) N3 26.5(16) 29.7(18) 36.7(18)−7.9(15)  8.5(14) −3.4(14) O3 16.8(12) 26.5(15) 44.4(17) 11.0(12) 5.0(11) −0.6(10) S3 20.4(4)  22.5(4)  31.7(4)  1.9(3)  8.4(3)  −0.2(3) C4 18.9(16) 16.8(18) 33.7(19) 2.6(14) 6.8(14) −1.6(13) N4 18.8(14)24.7(16) 26.1(15) 2.6(12) 9.4(12) −0.7(12) O4 21.0(13) 26.6(15) 35.0(15)7.7(11) 9.8(11)  1.9(10) C5 15.4(15) 19.8(18) 28.1(18) 1.4(14) 5.8(13)−1.8(12) N5 15.9(14) 19.5(15) 32.6(17) 6.3(12) 8.2(12)  0.9(11) O518.1(12) 22.0(14) 44.8(17) 6.8(12) 9.1(11)  2.9(10) C6 18.6(16) 18.3(17)25.1(17) 0.2(13) 6.7(13) −3.2(13) N6 13.7(13) 17.6(15) 29.7(14) 3.2(12)3.9(11) −0.3(11) C7 14.8(15) 16.3(16) 30.7(18) 2.8(14) 7.9(13)  1.1(12)N7 24.6(16)  47(2) 28.8(16) 2.6(15) 10.8(13)   0.8(15) C8 18.3(16)19.7(18) 30.7(19) 1.5(14) 6.3(14) −1.2(13) N8 16.3(14) 21.1(15) 33.0(16)4.9(13) 9.0(12)  1.3(11) C9 18.7(17) 19.7(18) 29.3(19) −0.5(14)  8.7(14)−1.9(13) N9 18.7(15) 21.7(17)  46(2) 5.6(14) 9.4(14) −1.0(12) C1016.6(17) 23.2(19) 31.9(19) −2.1(15)  6.2(14) −1.3(13) C11 22.0(18) 26(2) 28.2(18) 1.0(15) 3.3(14)  1.4(14) C12 24.5(18) 25.6(19) 26.6(18)3.5(15) 7.6(14) −1.6(14) O12 23.3(13) 34.5(16) 32.5(15) 1.8(12) 9.8(11)−0.5(11) C13 17.8(17)  28(2) 29.5(18) 3.4(15) 7.5(14) −1.7(14) O1336.8(16) 27.5(16) 38.2(16) −3.3(12)  9.4(13) −11.1(12)  C14 15.8(17)24.1(19) 31.0(19) 1.3(15) 5.3(14)  0.0(13) O14 29.6(15) 31.2(17)53.8(19) 11.2(14)  21.2(14)  10.2(13) C15 17.1(17)  31(2)  35(2)−2.2(17)  7.2(15)  0.4(15) C16 16.0(17)  41(2)  38(2) 9.6(18) 7.2(15) 6.0(16) O16 37.0(17) 40.7(19) 47.0(19) −9.1(15)  15.4(15)   1.6(14) C1718.0(16) 17.7(18) 28.7(18) 1.9(14) 7.4(14) −0.5(13) C18 12.5(15)19.0(17) 30.1(18) 1.2(14) 6.6(13) −2.0(12) C19 22.3(17) 22.8(19)30.0(19) −2.1(15)  9.0(14) −3.7(14) C20 25.3(18) 21.5(19) 28.1(18)−1.6(15)  7.8(14) −2.0(14) C21  29(2)  28(2)  32(2) −3.8(16)  10.0(16) −3.4(16) C22  29(2)  31(2)  32(2) −3.4(16)  12.5(16)  −1.2(16) C2319.0(17) 18.5(18) 31.7(19) 1.1(14) 8.8(14) −2.8(13) C24 14.5(16)22.5(18) 29.5(18) 2.6(14) 6.7(13)  0.0(13) C25 16.2(17) 21.5(18)27.8(17) 4.2(14) 7.1(13)  1.6(13) C26 24.9(18)  27(2) 30.3(19) 2.0(16)7.0(15) −2.1(15) C27  45(2)  20(2)  30(2) −1.2(16)  8.8(18) −2.0(17) C28 87(4)  32(3)  32(2) −2(2)   1(3)  21(3) C29 174(9)   16(3)  30(3)−4.3(19)  −7(4)   10(4) C30 159(9)   54(4)  40(3) −14(3)  36(5)  −55(5) C31 104(6)   89(6)  41(3) −12(4)  35(4)  −55(5)  C32  55(3)  44(3) 36(2) −9(2)  20(2)  −16(2)  C47 21.2(17) 24.5(19) 31.6(19) 4.3(15)8.0(14) −2.5(14) C48  32(2)  28(2)  31(2) 2.5(16) 7.2(16) −3.7(16) C49 35(2)  37(3)  36(2) 8.1(19) 7.1(18) −6.9(18) C50  28(2)  31(2)  47(3)12.9(19)  7.5(18) −2.4(16) C51  43(2)  20(2)  52(3) 2.0(19) 11(2) −4.2(18) C52  38(2)  24(2)  36(2) 0.1(17) 11.6(18)  −5.2(17) C53  49(3) 39(3)  64(3) 23(3)   5(3) −13(2)  S1 23.6(4)  20.0(4)  34.3(5) −2.5(4)  10.4(3)  −1.5(3)  O6 25.2(14) 17.9(13) 44.8(16) −1.0(12) 11.5(12)   1.5(11) O7 25.7(14) 30.2(16) 44.0(17) −3.6(13)  14.3(12) −6.0(12) O8 36.6(16) 29.3(16) 32.8(15) −6.1(12)  9.3(13) −2.7(12) C3327.4(19) 17.2(18)  35(2) −0.7(15)  10.8(16)   2.5(14) C34 25.9(19) 28(2)  38(2) −2.5(17)  5.4(17) −1.7(15) C35  37(2)  32(2)  36(2)1.7(18) 4.8(18)  1.6(18) C36  40(2)  27(2)  38(2) 6.8(18) 8.8(18) 3.8(17) C37  36(2)  21(2)  44(2) −0.4(17)  10.6(18)  −3.6(16) C38 29(2) 20.8(19)  38(2) −2.1(16)  6.7(16) −3.6(15) C39  66(4)  47(3) 47(3) 17(3)  12(3)   −4(3) S2 23.1(4)  28.2(5)  37.7(5)  11.5(4) 2.7(4)  −5.4(4)  O9 24.7(17)  64(3) 118(4)  64(3)   2(2)  4.4(17) O10117(4)   65(3) 34.3(18) −14.0(18)  37(2)  −54(3)  O11 21.5(13) 39.0(18)40.5(17) 8.4(13) 8.9(12) −5.8(12) C40 20.2(17) 17.4(18)  38(2) 5.5(15)10.3(15)   0.7(14) C41  30(2)  27(2)  34(2) 1.4(16) 9.4(16) −6.1(16) C42 37(2)  25(2)  42(2) 3.6(18) 15.4(18)  −6.4(17) C43 25.4(19)  34(2) 45(2) −0.3(19)  18.1(18)   3.2(16) C44  38(2)  43(3)  44(3) −13(2) 21(2)   −8(2) C45  34(2)  27(2)  52(3) −9.1(19)  22(2)  −5.7(17) C46 46(3)  55(3)  47(3)  8(2) 28(2)   3(2) O15 28.2(14) 34.7(17) 36.4(16)1.9(13) 10.5(12)   2.2(12) C54  54(3)  36(3)  45(3) −1(2)  12(2)   0(2)

TABLE 24 Bond Lengths for MTP-131 Tosylate, Pattern 2. Atom AtomLength/Å Atom Atom Length/Å C1 N1 1.338(6) C21 C22 1.515(6) C1 N21.322(6) C24 C25 1.540(5) C1 N3 1.336(6) C24 C26 1.555(6) O1 C6 1.227(5)C26 C27 1.506(6) C2 C3 1.527(6) C27 C28 1.396(7) C2 N3 1.459(6) C27 C321.388(8) O2 C12 1.381(5) C28 C29 1.449(11) C3 C4 1.520(5) C29 C301.359(15) O3 C17 1.237(5) C30 C31 1.330(15) S3 O12 1.472(3) C31 C321.390(8) S3 O13 1.453(3) C47 C48 1.390(6) S3 O14 1.457(3) C47 C521.392(6) S3 C47 1.763(4) C48 C49 1.389(6) C4 C5 1.532(5) C49 C501.396(7) N4 C5 1.501(5) C50 C51 1.394(8) O4 C23 1.225(5) C50 C531.509(7) C5 C6 1.538(5) C51 C52 1.403(7) N5 C6 1.341(5) S1 O6 1.469(3)N5 C7 1.460(5) S1 O7 1.468(3) O5 C25 1.238(5) S1 O8 1.469(3) N6 C171.334(5) S1 C33 1.757(4) N6 C18 1.461(4) C33 C34 1.397(6) C7 C8 1.548(5)C33 C38 1.395(6) C7 C17 1.525(5) C34 C35 1.395(7) N7 C22 1.498(6) C35C36 1.393(7) C8 C9 1.515(5) C36 C37 1.386(7) N8 C23 1.345(5) C36 C391.509(7) N8 C24 1.462(5) C37 C38 1.388(7) C9 C10 1.400(6) S2 O9 1.464(4)C9 C14 1.407(5) S2 O10 1.453(5) N9 C25 1.328(5) S2 O11 1.456(3) C10 C111.395(6) S2 C40 1.761(4) C10 C15 1.511(5) C40 C41 1.391(6) C11 C121.387(6) C40 C45 1.399(7) C12 C13 1.392(6) C41 C42 1.391(6) C13 C141.395(6) C42 C43 1.395(7) C14 C16 1.518(5) C43 C44 1.388(7) C18 C191.541(5) C43 C46 1.511(7) C18 C23 1.529(5) C44 C45 1.385(7) C19 C201.527(6) O15 C54 1.432(6) C20 C21 1.526(6)

TABLE 25 Bond Angles for MTP-131 Tosylate, Pattern 2. Atom Atom AtomAngle/° Atom Atom Atom Angle/° N2 C1 N1 120.0(4) C25 C24 C26 110.2(3) N2C1 N3 122.2(4) O5 C25 N9 123.5(3) N3 C1 N1 117.8(4) O5 C25 C24 118.7(3)N3 C2 C3 114.4(4) N9 C25 C24 117.8(3) C4 C3 C2 109.4(3) C27 C26 C24114.9(3) C1 N3 C2 126.5(4) C28 C27 C26 121.1(5) O12 S3 C47 105.9(2) C32C27 C26 121.0(4) O13 S3 O12 111.59(18) C32 C27 C28 117.9(5) O13 S3 O14113.3(2) C27 C28 C29 118.0(7) O13 S3 C47 105.7(2) C30 C29 C28 121.4(7)O14 S3 O12 112.1(2) C31 C30 C29 119.6(6) O14 S3 C47 107.64(19) C30 C31C32 121.4(8) C3 C4 C5 114.4(3) C27 C32 C31 121.7(7) C4 C5 C6 113.2(3)C48 C47 S3 119.1(3) N4 C5 C4 110.7(3) C48 C47 C52 120.7(4) N4 C5 C6107.2(3) C52 C47 S3 120.2(3) C6 N5 C7 121.8(3) C49 C48 C47 119.2(4) O1C6 C5 121.0(3) C48 C49 C50 121.6(5) O1 C6 N5 125.0(4) C49 C50 C53120.6(5) N5 C6 C5 113.9(3) C51 C50 C49 118.4(4) C17 N6 C18 121.7(3) C51C50 C53 120.9(5) N5 C7 C8 109.5(3) C50 C51 C52 120.8(5) N5 C7 C17108.3(3) C47 C52 C51 119.3(4) C17 C7 C8 109.8(3) O6 S1 C33 104.48(18) C9C8 C7 111.2(3) O7 S1 O6 111.57(18) C23 N8 C24 123.9(3) O7 S1 O8113.15(19) C10 C9 C8 119.8(3) O7 S1 C33 107.5(2) C10 C9 C14 119.1(4) O8S1 O6 112.32(19) C14 C9 C8 121.0(3) O8 S1 C33 107.2(2) C9 C10 C15120.4(4) C34 C33 S1 120.1(3) C11 C10 C9 120.6(3) C38 C33 S1 118.9(3) C11C10 C15 118.9(4) C38 C33 C34 120.6(4) C12 C11 C10 119.7(4) C35 C34 C33119.1(4) O2 C12 C11 122.8(4) C36 C35 C34 121.0(4) O2 C12 C13 116.8(3)C35 C36 C39 119.5(5) C11 C12 C13 120.4(4) C37 C36 C35 118.7(4) C12 C13C14 120.2(3) C37 C36 C39 121.7(5) C9 C14 C16 122.2(4) C36 C37 C38121.7(4) C13 C14 C9 119.7(4) C37 C38 C33 118.9(4) C13 C14 C16 118.1(3)O9 S2 C40 105.4(2) O3 C17 N6 124.6(3) O10 S2 O9 114.7(4) O3 C17 C7119.1(3) O10 S2 O11 113.1(3) N6 C17 C7 116.2(3) O10 S2 C40 106.2(2) N6C18 C19 112.8(3) O11 S2 O9 110.2(2) N6 C18 C23 109.7(3) O11 S2 C40106.47(19) C23 C18 C19 107.5(3) C41 C40 S2 121.2(3) C20 C19 C18 112.9(3)C41 C40 C45 119.2(4) C21 C20 C19 112.2(3) C45 C40 S2 119.6(3) C22 C21C20 113.7(4) C42 C41 C40 119.7(4) N7 C22 C21 112.8(3) C41 C42 C43121.3(4) O4 C23 N8 123.9(4) C42 C43 C46 121.4(5) O4 C23 C18 122.4(3) C44C43 C42 118.3(4) N8 C23 C18 113.6(3) C44 C43 C46 120.3(5) N8 C24 C25105.0(3) C45 C44 C43 121.0(5) N8 C24 C26 110.5(3) C44 C45 C40 120.4(4)

TABLE 26 Torsion Angles for MTP-131 Tosylate, Pattern 2. A B C D Angle/°A B C D Angle/° N1 C1 N3 C2 −176.7(4) C19 C20 C21 C22 −171.8(3) C2 C3 C4C5 173.3(3) C20 C21 C22 N7 −61.7(5) N2 C1 N3 C2 1.5(7) C23 N8 C24 C25−158.7(4) O2 C12 C13 C14 −178.9(4) C23 N8 C24 C26 82.4(5) C3 C2 N3 C177.9(6) C23 C18 C19 C20 177.0(3) C3 C4 C5 N4 −66.2(4) C24 N8 C23 O4−4.8(6) C3 C4 C5 C6 54.2(4) C24 N8 C23 C18 170.1(3) N3 C2 C3 C4 166.6(3)C24 C26 C27 C28 100.0(5) S3 C47 C48 C49 177.0(3) C24 C26 C27 C32−80.4(5) S3 C47 C52 C51 −176.9(4) C25 C24 C26 C27 69.4(5) C4 C5 C6 O1−112.4(4) C26 C24 C25 O5 83.9(4) C4 C5 C6 N5 66.6(4) C26 C24 C25 N9−95.6(4) N4 C5 C6 O1 10.0(5) C26 C27 C28 C29 179.9(4) N4 C5 C6 N5−171.0(3) C26 C27 C32 C31 −179.7(5) N5 C7 C8 C9 −174.8(3) C27 C28 C29C30 −0.6(9) N5 C7 C17 O3 −44.7(5) C28 C27 C32 C31 −0.1(8) N5 C7 C17 N6136.6(3) C28 C29 C30 C31 0.5(10) C6 N5 C7 C8 111.1(4) C29 C30 C31 C32−0.2(10) C6 N5 C7 C17 −129.3(4) C30 C31 C32 C27 0.0(10) N6 C18 C19 C20−61.9(4) C32 C27 C28 C29 0.3(7) N6 C18 C23 O4 −51.9(5) C47 C48 C49 C500.0(7) N6 C18 C23 N8 133.2(3) C48 C47 C52 C51 0.8(7) C7 N5 C6 O1 6.6(6)C48 C49 C50 C51 0.6(7) C7 N5 C6 C5 −172.4(3) C48 C49 C50 C53 −178.8(5)C7 C8 C9 C10 82.5(4) C49 C50 C51 C52 −0.5(7) C7 C8 C9 C14 −96.1(4) C50C51 C52 C47 −0.1(7) C8 C7 C17 O3 74.8(5) C52 C47 C48 C49 −0.7(7) C8 C7C17 N6 −103.9(4) C53 C50 C51 C52 178.8(5) C8 C9 C10 C11 −174.7(4) S1 C33C34 C35 171.4(3) C8 C9 C10 C15 7.6(6) S1 C33 C38 C37 −171.9(3) C8 C9 C14C13 173.3(4) O6 S1 C33 C34 −93.9(4) C8 C9 C14 C16 −9.6(6) O6 S1 C33 C3878.7(4) N8 C24 C25 O5 −35.1(5) O7 S1 C33 C34 24.8(4) N8 C24 C25 N9145.4(4) O7 S1 C33 C38 −162.6(3) N8 C24 C26 C27 −174.9(3) O8 S1 C33 C34146.7(3) C9 C10 C11 C12 0.3(6) O8 S1 C33 C38 −40.7(4) C10 C9 C14 C13−5.3(6) C33 C34 C35 C36 1.0(7) C10 C9 C14 C16 171.7(4) C34 C33 C38 C370.7(6) C10 C11 C12 O2 177.6(4) C34 C35 C36 C37 −0.5(7) C10 C11 C12 C13−3.4(6) C34 C35 C36 C39 179.8(5) C11 C12 C13 C14 2.0(6) C35 C36 C37 C380.0(7) C12 C13 C14 C9 2.4(6) C36 C37 C38 C33 −0.1(7) C12 C13 C14 C16−174.8(4) C38 C33 C34 C35 −1.1(6) O12 S3 C47 C48 160.1(3) C39 C36 C37C38 179.7(5) O12 S3 C47 C52 −22.2(4) S2 C40 C41 C42 −178.1(4) O13 S3 C47C48 41.5(4) S2 C40 C45 C44 177.0(4) O13 S3 C47 C52 −140.7(4) O9 S2 C40C41 −109.5(4) C14 C9 C10 C11 4.0(6) O9 S2 C40 C45 71.2(4) C14 C9 C10 C15−173.8(4) O10 S2 C40 C41 12.7(5) O14 S3 C47 C48 −79.8(4) O10 S2 C40 C45−166.7(4) O14 S3 C47 C52 97.9(4) O11 S2 C40 C41 133.5(4) C15 C10 C11 C12178.1(4) O11 S2 C40 C45 −45.8(4) C17 N6 C18 C19 99.9(4) C40 C41 C42 C431.4(7) C17 N6 C18 C23 −140.2(4) C41 C40 C45 C44 −2.4(7) C17 C7 C8 C966.4(4) C41 C42 C43 C44 −2.7(7) C18 N6 C17 O3 −5.0(6) C41 C42 C43 C46175.3(5) C18 N6 C17 C7 173.6(3) C42 C43 C44 C45 1.5(7) C18 C19 C20 C21−172.4(3) C43 C44 C45 C40 1.0(8) C19 C18 C23 O4 71.2(5) C45 C40 C41 C421.2(6) C19 C18 C23 N8 −103.7(4) C46 C43 C44 C45 −176.5(5)

TABLE 27 Hydrogen Atom Coordinates (Å × 104) and Isotropic DisplacementParameters (Å2 × 103) for MTP-131 Tosylate, Pattern 2. Atom x y z U(eq)H1A 11245.32 7066.87 4979.6 39 H1B 9460.92 7167.19 5072.65 39 H2A7407.71 6978.75 2061.35 35 H2B 5678.96 6988.1 2381.78 35 H2C 10141.746745.9 2707.92 39 H2D 11658.15 6824.44 3535.93 39 H2 2357.75 4379.127205.77 48 H3A 7717.66 6139.45 2303.32 30 H3B 6270.67 6125.63 2860.46 30H3 7185.9 7074.64 3848.91 37 H4A 5545.55 6382.18 914.69 28 H4B 4146.66301.27 1483.26 28 H4C 6448.25 5212.86 453.9 27 H4D 7475.93 5372.511380.22 27 H4E 7141.43 5713.7 581.17 27 H5 4114.12 5612.97 537.26 25 H5A2487.02 5556.72 1722.91 27 H6 1770.53 4246.24 3120.35 25 H7 3655.234850.28 3119.99 24 H7A −1943.9 4457.65 −1801.68 39 H7B −2005.94 4561.59−831.16 39 H7C −3312.76 4245.65 −1431.11 39 H8A 3763.61 5668.69 3818.2527 H8B 1753.94 5715.13 3396.7 27 H8 −3200.02 4124.91 3330.78 28 H9A−7135.56 3273.76 4023.6 34 H9B −5511.79 2985.59 4394.76 34 H11 4463.154614.87 6397.35 31 H13 −658.63 4859.62 5483.54 30 H15A 5757.19 4973.634525.77 42 H15B 6420.71 4946.46 5635.22 42 H15C 5860.02 5456.96 5136.0842 H16A −543.84 5793.7 3971.44 47 H16B −1797.68 5428.73 4306.7 47 H16C−1138.7 5302.18 3407.42 47 H16D −66.12 5377.61 10152.89 61 H16E −132.025207.14 9244.45 61 H18 −1732.19 4381.06 2403.6 24 H19A −80.45 3525.521887.97 30 H19B −2094.76 3596.94 1637.67 30 H20A −1756.24 4298.51 681.8330 H20B 208.5 4159.53 861.33 30 H21A −680.52 3373.29 115.92 35 H21B−2587.52 3571.84 −157.42 35 H22A 115.08 3980.68 −843.57 36 H22B −1340.773636.77 −1444.2 36 H24 −2772.96 3249.33 4280.77 26 H26A −1099.65 3824.015454.71 33 H26B −2792.63 4130.95 5380.63 33 H28 −441.83 3124.52 6535.0763 H29 −1213.38 2652.38 7749.48 96 H30 −3861.13 2745.33 8054.93 99 H31−5802.4 3279.66 7186.87 90 H32 −5163.73 3744.07 5996.13 52 H48 4201.744197.16 11182.46 37 H49 3847.4 3502.52 12046.16 43 H51 2664.51 2686.189664.29 46 H52 3020.91 3382.69 8783.17 39 H53A 3576.36 2618.08 12173.3478 H53B 3360.44 2282.36 11271.36 78 H53C 1735.19 2535.85 11487.56 78 H3417066.6 6826.98 6909.77 37 H35 16742.25 6351.6 8185.52 43 H37 12408.745752.62 6556.43 40 H38 12673.65 6227.11 5276.34 35 H39A 14220.34 5908.428837.68 80 H39B 15406.58 5499.26 8568.07 80 H39C 13393.65 5476.6 8149.680 H41 1711.37 7354.12 373.89 36 H42 2681.46 7703.19 −848.11 40 H44776.35 6553.74 −2533.29 47 H45 −114.62 6187.87 −1306.81 43 H46A 1257.077536.27 −3107.11 69 H46B 2872.15 7186.42 −2960.85 69 H46C 3033.297696.61 −2429.21 69 H15 −524.45 4644.58 −2896.74 49 H54A −1102.045458.59 −3226.65 68 H54B 60.96 5343.02 −2207.44 68 H54C −1929.74 5436.02−2359.74 68

TABLE 28 MTP-131 tosylate, Pattern 2 simulated XRPD 2θ diffractogram.Relative Pos. d-spacing Height Area intensity No. [°2θ] FWHM [Å] [cts][cts**2θ] [%] 1 6.5499 0.120 1361.24 13.4840 8507.75 84.60 2 7.07860.096 680.42 12.4779 5315.76 52.86 3 9.0752 0.096 328.28 9.7367 2564.6625.50 4 11.5768 0.096 294.80 7.6377 2303.15 22.90 5 11.9091 0.072 232.297.4253 2419.71 24.06 6 12.0299 0.096 541.85 7.3510 4233.19 42.09 712.5679 0.120 248.93 7.0375 1555.79 15.47 8 13.1228 0.096 821.13 6.74126415.1 63.79 9 13.3092 0.096 698.76 6.6472 5459.09 54.28 10 14.18710.096 131.66 6.2377 1028.61 10.23 11 14.4172 0.072 266.65 6.1387 2777.5727.62 12 14.5545 0.096 365.94 6.0811 2858.91 28.43 13 14.7572 0.144251.09 5.9981 1307.76 13.00 14 15.1094 0.120 592.42 5.8590 3702.59 36.8215 15.8496 0.096 1217.01 5.5870 9507.91 94.54 16 15.9777 0.072 830.345.5425 8649.42 86.01 17 17.4741 0.120 1497.64 5.0711 9360.24 93.08 1817.7285 0.072 232.80 4.9989 2425.04 24.11 19 19.5391 0.096 1024.464.5396 8003.59 79.59 20 19.7411 0.096 1016.14 4.4936 7938.61 78.94 2120.0464 0.072 205.14 4.4258 2136.84 21.25 22 20.1613 0.144 479.44 4.40092497.07 24.83 23 20.5588 0.072 191.56 4.3167 1995.47 19.84 24 20.72830.120 924.72 4.2817 5779.52 57.47 25 21.3456 0.096 910.95 4.1593 7116.7770.77 26 22.1097 0.120 304.25 4.0172 1901.53 18.91 27 22.5050 0.096391.10 3.9476 3055.44 30.38 28 22.9420 0.096 506.23 3.8734 3954.95 39.3329 23.2455 0.120 1609.04 3.8235 10056.52 100.00 30 23.4775 0.120 365.653.7862 2285.33 22.72 31 23.9349 0.120 1080.26 3.7149 6751.62 67.14 3224.3856 0.096 331.44 3.6472 2589.41 25.75 33 24.5609 0.096 259.52 3.62162027.48 20.16 34 25.1486 0.072 167.93 3.5383 1749.28 17.39 35 25.29400.096 295.35 3.5183 2307.4 22.94 36 25.5145 0.096 247.46 3.4883 1933.319.22 37 25.6168 0.072 185.57 3.4747 1933.05 19.22 38 25.8367 0.096349.62 3.4456 2731.41 27.16 39 26.1158 0.144 208.44 3.4094 1085.62 10.8040 26.3529 0.096 210.87 3.3792 1647.39 16.38 41 26.5878 0.096 163.873.3499 1280.27 12.73 42 26.8797 0.096 163.85 3.3142 1280.09 12.73 4327.7376 0.072 105.35 3.2136 1097.43 10.91 44 28.4171 0.072 123.79 3.13831289.49 12.82 45 28.5966 0.096 411.07 3.1190 3211.5 31.93 46 28.91730.096 172.59 3.0851 1348.36 13.41 47 29.8379 0.072 153.78 2.9920 1601.8715.93

1. A crystalline form of a salt of Compound I,

wherein said crystalline form has characteristic peaks in its XRPDpattern at values of two theta as described in any one of Tables 1-20.2. A crystalline form of a salt of Compound I,

wherein said crystalline form has characteristic peaks in its XRPDpattern as described in any one of FIGS. 1-26.
 3. The crystalline formof claim 1, wherein the crystalline form has characteristic peaks in itsXRPD pattern at values of two theta as described in any one of Tables11-18.
 4. The crystalline form of claim 1, wherein the crystalline formhas characteristic peaks in its XRPD pattern at values of two theta asdescribed in any one of Tables 5, 6, 9 and
 10. 5. The crystalline formof claim 1, wherein the crystalline form has characteristic peaks in itsXRPD pattern at values of two theta as described in any one of Tables1-2, 3-4, 7-8, 19 and
 20. 6.-45. (canceled)
 46. A composition,comprising a crystalline form of claim
 1. 47. A process for making apharmaceutical composition comprising Compound I,

comprising dissolving a crystalline form of claim
 1. 48. A composition,comprising a crystalline form of claim
 2. 49. A composition, comprisinga crystalline form of claim
 3. 50. A composition, comprising acrystalline form of claim
 4. 51. A composition, comprising a crystallineform of claim
 5. 52. A process for making a pharmaceutical compositioncomprising Compound I,

comprising dissolving a crystalline form of claim
 2. 53. A process formaking a pharmaceutical composition comprising Compound I,

comprising dissolving a crystalline form of claim
 3. 54. A process formaking a pharmaceutical composition comprising Compound I,

comprising dissolving a crystalline form of claim
 4. 55. A process formaking a pharmaceutical composition comprising Compound I,

comprising dissolving a crystalline form of claim 5.